3,4-diaryl thiopenes and analogs thereof having use as antiinflammatory agents

ABSTRACT

A class of 3,4-diaryl substituted thiophene, furan and pyrrole derivatives and analogs thereof, pharmaceutical compositions containing them and methods of using them to treat inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula I:                    
     wherein Y is selected from O, S and NR 1 ; wherein R 1  is selected from hydrido and lower alkyl; wherein X is one or two substituent selected from hydrido, halo, lower alkoxycarbonyl and carboxyl; wherein R 2  and R 3  are independently aryl or heteroaryl; and wherein R 2  and R 3  are optionally substituted at a substitutable position with one or more radicals selected from sulfamyl, alkylsulfonyl, halo, lower alkoxy and lower alkyl; or a pharmaceutically-acceptable salt thereof.

This application is a continuation of Ser. No. 09/528,654 Mar. 20, 2000abandoned, which is a continuation of Ser. No. 09/366,484 Aug. 3, 1999,abandoned, which is a continuation of Ser. No. 08/969,953 Nov. 25, 1997abandoned, which is a continuation of Ser. No. 08/464,722 Jun. 27, 1995abandoned, which is a CIP of Ser. No. 08/004,822 Jan. 15, 1993abandoned.

This invention is in the field of antiinflammatory pharmaceutical agentsand relates to compounds, compositions and methods for treatinginflammation and inflammation-associated disorders, such as arthritis.This invention specifically relates to 3,4-diaryl substituted thiophene,furan and pyrrole derivatives and analogs thereof. More particularly,this invention relates to selected effective and safe compounds havingantiinflammatory and/or analgesic activity without erosion of thestomach.

BACKGROUND OF THE INVENTION

Prostaglandins play a major role in the inflammation process, and theinhibition of prostaglandin production, especially production of PGG₂,PGH₂ and PGE₂, has been a common target of antiinflammatory drugdiscovery. However, common non-steroidal antiinflammatory drugs (NSAIDs)that are active in reducing the prostaglandin-induced pain and swellingassociated with the inflammation process, are also active in affectingother prostaglandin-regulated processes not associated with theinflammation process. Thus, use of high doses of most common NSAIDs canproduce severe side effects, including life-threatening ulcers, thatlimit their therapeutic potential. An alternative to NSAIDs is the useof corticosteroids, which have even more drastic side effects,especially when long-term therapy is involved.

Previous NSAIDs have been found to prevent the production ofprostaglandins by inhibiting enzymes in the human arachidonicacid/prostaglandin pathway, including the enzyme cyclooxygenase (COX).Recently, the sequence of another heretofore unknown enzyme in the humanarachidonic acid/prostaglandin pathway has been reported by T. Hla andK. Nielson, Proc. Natl. Acad. Sci. USA, 89, 7384 (1992) and named“cyclooxygenase II (COX II)” or “prostaglandin G/H synthase II”. Thediscovery of an inducible enzyme associated with inflammation provides aviable target of inhibition which more effectively reduces inflammationand produces fewer and less drastic side effects. Cyclooxygenase II isinducible by cytokines or endotoxins and such induction is inhibited byglucocortoids (J. Masferrer, et al, Proc. Natl. Acad. Sci. USA, 89, 3917(1992)). The 6-methoxy-2-napthylacetic acid metabolite of nabumetone hasbeen found by E. Meade et al to selectively inhibit the COX II enzyme(J. Biol. Chem., 268, 6610 (1993)). In addition, Futaki et al (Gen.Pharmac., 24, 105 (1993)) has reported thatN-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide is antiinflammatoryand lacks gastric side effects.

The substituted thiophene compounds disclosed herein selectively inhibitcyclooxygenase II over cyclooxygenase I and relieve the effects ofinflammation. These compounds, in addition, do not display substantialinhibition of cyclooxygenase I and produce a reduced amount of sideeffects.

Selected symmetrical 3,4-bis(phenyl, naphthyl or substituted phenyl)thiophenes are known.

Preparation of a wide-variety of asymmetric biaryl compounds includingsubstituted thiophene, furan and pyrrol heterocyles is described in U.S.Pat. No. 4,990,647 having a suggested utility as precursors forbrighteners, pharmaceuticals, plant protection active compounds andliquid crystal materials.

U.S. Pat. No. 4,757,084 describes to Biftu analogs of 2,5-diaryltetrahydrothiophenes having activity as PAF-antagonists which are saidto be linked to physiological processes associated with a large group ofdiseases including inflammatory disease.

U.S. Pat. No. 5,196,532 to Wuest et al, describes 2,4-diaryl substitutedthiophenes for cosmetics and the treatment of dermatological disorders.

U.S. Pat. No. 4,427,693 to Haber, describes antiinflammatory4,5-diarylthiophene-2-methanamines. U.S. Pat. No. 4,432,974 to Haber,describes antiinflammatory and analgesic 2,3-diaryl-5-silylthiophenes.U.S. Pat. No. 4,302,461 to Cherkofsky, describes antiinflammatory2,3-diarylthiophenes substituted with various alkyl sulfur radicals atposition 5. U.S. Pat. No. 4,381,311 to Haber, describes antiinflammatory4,5-diarylthiophene-2-methanols.

2,3-Diaryl-5-halo thiophenes are described in U.S. Pat. No. 4,590,205 toHaber, as analgesic or antiinflammatory agents. 4-Fluorophenyl and4-methylsulfonylphenyl are among the various substituted phenyl groupsthat define the diaryl groups. U.S. Pat. No. 4,820,827 to Haber,describes 2,3-diaryl-5-bromo thiophenes, and specifically5-bromo-2-(4-methylthiophenyl)-3-(4-fluorophenyl)thiophene, as havingantiinflammatory and prostaglandin synthetase inhibitory activity foruse in the treatment of inflammation and dysmenorrhea.

Japanese publication 4,235,767 describes photosensitive3,4-bis(diazosubstitutedphenyl)thiophene pigments for use inphotocopiers or facsimile receivers.

U.S. Pat. No. 3,743,656 to Brown et al, a CIP of U.S. Pat. No.3,644,399, describes thiophene and furan derivatives havingantiinflammatory activity, including ethyl3,4-diphenylthiophene-2-propionate.

The above documents describing antiinflammatory activity show continuingefforts to find a safe and effective antiinflammatory agent.

DESCRIPTION OF THE INVENTION

A class of compounds useful in treating inflammation-related disordersis defined by Formula I:

wherein Y is selected from S, O, and NR¹;

wherein R¹ is selected from hydrido and C₁-C₆ alkyl;

wherein X is one or more substituents selected from

a) hydrido, halo, cyano, nitro, hydroxy, acyl, lower alkyl substitutedat a substitutable position with a substituent selected from halo,hydroxyl, amino, acylamino, lower alkylamino, lower alkyl(acyl)amino,acyl, aryl optionally substituted with hydroxyl, a heterocyclic group,hydroxyimino and lower alkoxyimino, lower alkenyl optionally substitutedat a substitutable position with cyano, amino optionally substituted ata substitutable position with a radical selected from acyl and loweralkylsulfonyl, sulfo, sulfamoyl optionally substituted with asubstituent selected from the group consisting of lower alkyl,halo(lower)alkyl, aryl, hydroxyl, lower alkylamino(lower)alkyl, aheterocyclic group and (esterified carboxy)lower alkyl, N-containingheterocyclicsulfonyl, a heterocyclic group optionally substituted at asubstitutable position with a substituent selected from the groupconsisting of hydroxyl, oxo, amino and lower alkylamino,

b) S(O)_(n)R⁵, wherein R⁵ is C₁-C₆ alkyl optionally substituted at asubstitutable position with fluoro, and n is 0, 1 or 2,

c) C(R⁶)(OR⁸)(R⁷) wherein R⁶ and R⁷ independently are selected from CF₃,CF₂H, CFCl₂, CF₂Cl, CClFH, CCl₂F, CF₃CF₂ and C₁-C₂ alkyl, and wherein R⁸is selected from hydrido, C₁-C₄ alkyl, (C₁-C₃ alkyl)C(O) and CO₂R⁹,wherein R⁹ is C₁-C₄ alkyl,

d) C(O)ZR⁴, wherein Z is O, N, or S, and R⁴ is selected from hydrido,C₁-C₆ alkyl and aryl, and when Z is N then R⁴ is independently takentwice,

e) C(R⁹)(NHR¹¹)(R¹⁰), wherein R⁹ and R¹⁰ are independently selected fromCF₃, CF₂H, CFCl₂, CF₂Cl, CClFH and CCl₂H, and R¹¹ is selected fromhydrido and C₁-C₃ alkyl, and

wherein R² and R³ are independently selected from aryl or heteroaryl,wherein the aryl or heteroaryl radical is optionally substituted at asubstitutable position with a radical selected from halo, lower alkyl,lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl,nitro, amide, amino, lower alkylamino, sulfamyl and loweralkylsulfonylamino;

 provided that at least one of R² or R³ is substituted with loweralkylsulfonyl or sulfamyl;

 or a pharmaceutically-acceptable salt thereof.

Compounds of Formula I would be useful for the treatment of inflammationin a subject, and for treatment of other inflammation-associateddisorders, for example, as an analgesic in the treatment of pain andheadaches, or as an antipyretic for the treatment of fever. For example,compounds of Formula I would be useful to treat arthritis, including butnot limited to rheumatoid arthritis, spondyloarthopathies, goutyarthritis, systemic lupus erythematosus, osteoarthritis and juvenilearthritis. Such compounds of Formula I would be useful in the treatmentof asthma, bronchitis, menstrual cramps, tendinitis, bursitis, and skinrelated conditions such as psoriasis, eczema, burns and dermatitis.Compounds of Formula I also would be useful to treat gastrointestinalconditions such as inflammatory bowel syndrome, Crohn's disease,gastritis, irritable bowel syndrome and ulcerative colitis. Compounds ofFormula I would be useful in treating inflammation in such diseases asvascular diseases, migraine headaches, periarteritis nodosa,thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumaticfever, type I diabetes, myasthenia gravis, sarcoidosis, nephroticsyndrome, Behcet's syndrome, polymyositis, hypersensitivity,conjunctivitis, gingivitis, swelling occurring after injury, myocardialischemia, and the like. The compounds are useful as antiinflammatoryagents, such as for the treatment of arthritis, with the additionalbenefit of having significantly less harmful side effects.

The present invention also includes compounds which selectively inhibitcyclooxygenase II over cyclooxygenase I and do not significantly inhibitone or more other arachidonic pathway steps, such as thromboxane B₂(TXB₂) production. Importantly, thromboxanes cause blood plateletaggregation and have vasoconstriction properties. Thus a lack of effectin the regulation of non-inflammation related thromboxane production isfurther evidence of the beneficial selectivity of the present compounds.

Preferably, the compounds of the present invention have a thromboxane B₂inhibition IC₅₀ of greater than about 1.5 μM, as determined by a wholecell assay and preferably over 10 μM. The inhibition of the productionof TXB₂ by a whole cell assay is a better indicator of potential in vivobehavior as the assay also incorporates such factors as cell transport.

More preferably, the compounds also have a selectivity ratio ofcyclooxygenase II inhibition over cyclooxygenase I inhibition of atleast 50 and preferably of at least 100. Such preferred selectivity mayindicate an ability to reduce the incidence of common NSAID-induced sideeffects, such as ulcers.

The above mentioned aspects of the current invention exclude compoundssuch as 5-bromo-2-(4-methylthiophenyl)-3-(4-fluorophenyl)thiophene andN-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide.

A preferred class of compounds consists of those compounds of Formula Iwherein X is one or two substituents selected from hydrido, halo, cyano,nitro, hydroxyl, acyl, lower alkyl substituted at a substitutableposition with a substituent selected from halo, hydroxyl, amino,acylamino, lower alkylamino, lower alkyl(acyl)amino, acyl, aryloptionally substituted with hydroxyl, a heterocyclic group, hydroxyiminoand lower alkoxyimino, lower alkenyl optionally substituted at asubstitutable position with cyano, amino optionally substituted at asubstitutable position with a radical selected from acyl and loweralkylsulfonyl, sulfo, sulfamoyl optionally substituted with asubstituent selected from the group consisting of lower alkyl,halo(lower)alkyl, aryl, hydroxyl, lower alkylamino(lower)alkyl, aheterocyclic group and (esterified carboxy)lower alkyl, N-containingheterocyclicsulfonyl, a heterocyclic group optionally substituted at asubstitutable position with a substituent selected from the groupconsisting of hydroxyl, oxo, amino and lower alkylamino; and wherein R²and R³ are independently selected from aryl and heteroaryl, wherein thearyl or heteroaryl radical is optionally substituted at a substitutableposition with a radical selected from halo, lower alkyl, lower alkoxy,lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro, amino,amide, lower alkylamino, sulfamyl and lower alkylsulfonylamino; or apharmaceutically-acceptable salt thereof, provided that at least one ofR² or R³ is substituted with lower alkylsulfonyl or sulfamyl.

A more preferred class of compounds consists of those compounds ofFormula I wherein Y is S or O; wherein X is one or two substituentsselected from hydrido, halo, cyano, nitro, hydroxyl, carboxy, loweralkoxycarbonyl, lower alkyl substituted at a substitutable position witha substituent selected from halo, hydroxyl, amino, acylamino, loweralkylamino, lower alkyl(acyl)amino, lower alkoxycarbonyl, carboxy, aheterocyclic group, hydroxyimino and lower alkoxyimino, lower alkenyloptionally substituted at a substitutable position with cyano, aminooptionally substituted at a substitutable position with a radicalselected from acyl and lower alkylsulfonyl, sulfo, sulfamoyl optionallysubstituted with a substituent selected from the group consisting oflower alkyl, halo(lower)alkyl, aryl, hydroxyl, loweralkylamino(lower)alkyl, a heterocyclic group and (alkoxycarbonyl)loweralkyl, N-containing heterocyclicsulfonyl, a heterocyclic groupoptionally substituted at a substitutable position with a substituentselected from the group consisting of hydroxyl, oxo, amino and loweralkylamino; and wherein R² and R³ are independently selected from aryland heteroaryl, wherein the aryl or heteroaryl radical is optionallysubstituted at a substitutable position with a radical selected fromhalo, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl,lower alkylsulfonyl, nitro, amino, amide, lower alkylamino, sulfamyl andlower alkylsulfonylamino; or a pharmaceutically-acceptable salt thereof,provided that at least one of R² or R³ is substituted with loweralkylsulfonyl or sulfamyl.

A class of compounds of particular interest consists of those compoundsof Formula I wherein X is one or two substituents selected from hydrido,fluoro, chloro, bromo and iodo; or a pharmaceutically-acceptable saltthereof.

A family of specific compounds of particular interest within Formula Iconsists of compounds and pharmaceutically-acceptable salts thereof asfollows:

3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)thiophene;

4-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)-2,5-dibromothiophene;

4-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)-2-bromothiophene;

4-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)-2,5-difluorothiophene;

4-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)-2-fluorothiophene;

4-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)-2,5-dichlorothiophene;

4-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)-2-chlorothiophene;

ethyl[3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)thien-2-yl]carboxylate;

2-ethoxycarbonyl-4-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)thienyl-5-carboxylicacid;

methyl[3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)thien-2-yl]carboxylate;

2-methoxycarbonyl-4-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)thienyl-5-carboxylicacid;

4-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)thienyl-2,5-dicarboxylicacid;

3-(4-methylsulfonylphenyl)-4-(4-chlorophenyl)thiophene;

4-(4-methylsulfonylphenyl)-3-(4-chlorophenyl)-2,5-dibromothiophene;

4-(4-methylsulfonylphenyl)-3-(4-chlorophenyl)-2-bromothiophene;

3-(4-methylsulfonylphenyl)-4-(4-bromophenyl)thiophene;

3-(4-methylsulfonylphenyl)-4-(4-methoxyphenyl)thiophene;

4-(4-methylsulfonylphenyl)-3-(4-methoxyphenyl)-2-bromothiophene;

3-(4-methylsulfonylphenyl)-4-(4-ethoxyphenyl)thiophene;

4-(4-methylsulfonylphenyl)-3-(4-ethoxyphenyl)-2-bromothiophene;

3-(4-methanesulfonylphenyl)-4-phenyl-thiophene;

4-(4-methylsulfonylphenyl)-3-phenyl-2,5-dibromothiophene;

4-(4-methylsulfonylphenyl)-3-phenyl-2-bromothiophene;

3-(4-methanesulfonylphenyl)-4-(4-methylphenyl)thiophene;

4-(4-methylsulfonylphenyl)-3-(4-methylphenyl)-2,5-dibromothiophene;

4-(4-methylsulfonylphenyl)-3-(4-methylphenyl)-2-bromothiophene;

3-(4-methylsulfonylphenyl)-4-(2-methyl-4-fluorophenyl)thiophene;

3,4-bis(4-methoxyphenyl)thiophene;

2-fluoro-5-[3-(4-methylsulfonylphenyl)thien-4-yl]pyridine;

2-methyl-5-[3-(4-methylsulfonylphenyl)thien-4-yl]pyridine;

2-chloro-5-[3-(4-methylsulfonylphenyl)thien-4-yl]pyridine;

5-[3-(4-methylsulfonylphenyl)thien-4-yl]pyridine;

2-methoxy-5-[3-(4-methylsulfonylphenyl)thien-4-yl]pyridine;

2-fluoro-5-[3-(4-methylsulfonylphenyl)-2,5-dibromothien-4-yl]pyridine;

2-fluoro-5-[4-(4-methylsulfonylphenyl)-2-bromothien-3-yl]pyridine;

4-[4-(4-fluorophenyl)thien-3-yl]benzenesulfonamide;

4-[3-(4-fluorophenyl)-2,5-dibromo-thien-4-yl]benzenesulfonamide;

4-[3-(4-fluorophenyl)-2-bromo-thien-4-yl]benzenesulfonamide;

4-[4-(4-fluorophenyl)-2,5-difluoro-thien-3-yl]benzenesulfonamide;

4-[3-(4-fluorophenyl)-2-fluoro-thien-4-yl]benzenesulfonamide;

4-[4-(4-fluorophenyl)-2,5-dichloro-thien-3-yl]benzenesulfonamide;

4-[3-(4-fluorophenyl)-2-chloro-thien-4-yl]benzenesulfonamide;

4-[4-(4-fluorophenyl)-2-ethoxycarbonyl-thien-3-yl]benzenesulfonamide;

[4-(4-fluorophenyl)-2-ethoxycarbonyl-(4-aminosulfonylphenyl)thienyl]-5-carboxylicacid;

4-[4-(4-fluorophenyl)-2-methoxycarbonyl-thien-3-yl]benzenesulfonamide;

[4-(4-fluorophenyl)-2-methoxycarbonyl-(4-aminosulfonylphenyl)thienyl]-5-carboxylicacid;

[4-(4-fluorophenyl)-(4-aminosulfonylphenyl)thienyl]-2,5-dicarboxylicacid;

4-[4-(4-chlorophenyl)-thien-3-yl]benzenesulfonamide;

4-[3-(4-chlorophenyl)-2,5-dibromo-thien-4-yl]benzenesulfonamide;

4-[3-(4-chlorophenyl)-2-bromo-thien-4-yl]benzenesulfonamide;

4-[4-(4-bromophenyl)-thien-3-yl]benzenesulfonamide;

4-[4-(4-methoxyphenyl)-thien-3-yl]benzenesulfonamide;

4-[3-(4-methoxyphenyl)-2-bromo-thien-4-yl]benzenesulfonamide;

4-[4-(4-ethoxyphenyl)-thien-3-yl]benzenesulfonamide;

4-[3-(4-ethoxyphenyl)-2-bromo-thien-4-yl]benzenesulfonamide;

4-[4-phenyl-thien-3-yl]benzenesulfonamide;

4-[3-phenyl-2,5-dibromo-thien-4-yl]benzenesulfonamide;

4-[3-phenyl-2-bromo-thien-4-yl]benzenesulfonamide;

4-[4-(4-methylphenyl)-thien-3-yl]benzenesulfonamide;

4-[3-(4-methylphenyl)-2,5-dibromo-thien-4-yl]benzenesulfonamide;

4-[3-(4-methylphenyl)-2-bromo-thien-4-yl]benzenesulfonamide;

4-[4-(2-methyl-4-fluorophenyl)-thien-3-yl]benzenesulfonamide;

4-[4-(2-fluoropyridin-5-yl)-thien-3-yl]benzenesulfonamide;

4-[4-(2-methylpyridin-5-yl)-thien-3-yl]benzenesulfonamide;

4-[4-(2-chloropyridin-5-yl)-thien-3-yl]benzenesulfonamide;

4-[4-(pyridin-5-yl)-thien-3-yl]benzenesulfonamide;

4-[4-(2-methoxypyridin-5-yl)-thien-3-yl]benzenesulfonamide;

4-[4-(2-fluoropyridin-5-yl)-2,5-dibromo-thien-3-yl]benzenesulfonamide;

4-[4-(2-fluoropyridin-5-yl)-2-bromothien-3-yl]benzenesulfonamide;

3-(4-fluorophenyl)-4-(methylsulfonylphenyl)furan;

4-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)-2,5-dibromofuran;

4-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)-2-bromofuran;

ethyl[3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)fur-2-yl]carboxylate;

2-ethoxycarbonyl-4-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)thienyl-5-carboxylicacid;

methyl[3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)fur-2-yl]carboxylate;

2-methoxycarbonyl-4-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)thienyl-5-carboxylicacid;

4-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)thienyl-2,5-dicarboxylicacid;

3-(4-methylsulfonylphenyl)-4-(4-chlorophenyl)furan;

4-(4-methylsulfonylphenyl)-3-(4-chlorophenyl)-2,5-dibromofuran;

4-(4-methylsulfonylphenyl)-3-(4-chlorophenyl)-2-bromofuran;

4-(4-methylsulfonylphenyl)-3-(4-methoxyphenyl)furan;

4-(4-methylsulfonylphenyl)-3-(4-methoxyphenyl)-2-bromofuran;

3-(4-methylsulfonylphenyl)-4-(4-ethoxyphenyl)furan;

4-(4-methylsulfonylphenyl)-3-(4-ethoxyphenyl)-2-bromofuran;

3-(4-methanesulfonylphenyl)-4-phenyl-furan;

4-(4-methylsulfonylphenyl)-3-phenyl-2,5-dibromofuran;

4-(4-methylsulfonylphenyl)-3-phenyl-2-bromofuran;

3-(4-methanesulfonylphenyl)-4-(4-methylphenyl)furan;

4-(4-methylsulfonylphenyl)-3-(4-methylphenyl)-2,5-dibromofuran;

4-(4-methylsulfonylphenyl)-3-(4-methylphenyl)-2-bromofuran;

3-(4-methylsulfonylphenyl)-4-(2-methyl-4-fluorophenyl)furan;

2-fluoro-5-[3-(4-methylsulfonylphenyl)fur-4-yl]pyridine;

2-methyl-5-[3-(4-methylsulfonylphenyl)fur-4-yl]pyridine;

2-chloro-5-[3-(4-methylsulfonylphenyl)fur-4-yl]pyridine;

5-[3-(4-methylsulfonylphenyl)fur-4-yl]pyridine;

2-methoxy-5-[3-(4-methylsulfonylphenyl)fur-4-yl]pyridine;

2-fluoro-5-[3-(4-methylsulfonylphenyl)-2,5-dibromofur-4-yl]pyridine;

2-fluoro-5-[4-(4-methylsulfonylphenyl)-2-bromofur-3-yl]pyridine;

4-[4-(4-fluorophenyl)fur-3-yl]benzenesulfonamide;

4-[3-(4-fluorophenyl)-2,5-dibromo-fur-4-yl]benzenesulfonamide;

4-[3-(4-fluorophenyl)-2-bromo-fur-4-yl]benzenesulfonamide;

4-[4-(4-fluorophenyl)-2,5-difluoro-fur-3-yl]benzenesulfonamide;

4-[3-(4-fluorophenyl)-2-fluoro-fur-4-yl]benzenesulfonamide;

4-[4-(4-fluorophenyl)-2,5-dichloro-fur-3-yl]benzenesulfonamide;

4-[3-(4-fluorophenyl)-2-chloro-fur-4-yl]benzenesulfonamide;

4-[4-(4-fluorophenyl)-2-ethoxycarbonyl-fur-3-yl]benzenesulfonamide;

4-(4-fluorophenyl)-2-ethoxycarbonyl-(4-benzenesulfonamidyl)furyl-5-carboxylicacid;

4-[4-(4-fluorophenyl)-2-methoxycarbonyl-fur-3-yl]benzenesulfonamide;

4-(4-fluorophenyl)-2-methoxycarbonyl-(4-benzenesulfonamidyl)furyl-5-carboxylicacid;

4-(4-fluorophenyl)-(4-benzenesulfonamidyl)furyl-2,5-dicarboxylic acid;

4-[4-(4-chlorophenyl)-fur-3-yl]benzenesulfonamide;

4-[3-(4-chlorophenyl)-2,5-dibromo-fur-4-yl]benzenesulfonamide;

4-[3-(4-chlorophenyl)-2-bromo-fur-4-yl]benzenesulfonamide;

4-[4-(4-bromophenyl)-fur-3-yl]benzenesulfonamide;

4-[4-(4-methoxyphenyl)-fur-3-yl]benzenesulfonamide;

4-[3-(4-methoxyphenyl)-2-bromo-fur-4-yl]benzenesulfonamide;

4-[4-(4-ethoxyphenyl)-fur-3-yl]benzenesulfonamide;

4-[3-(4-ethoxyphenyl)-2-bromo-fur-4-yl]benzenesulfonamide;

4-[4-phenyl-fur-3-yl]benzenesulfonamide;

4-[3-phenyl-2,5-dibromo-fur-4-yl]benzenesulfonamide;

4-[3-phenyl-2-bromo-fur-4-yl]benzenesulfonamide;

4-[4-(4-methylphenyl)-fur-3-yl]benzenesulfonamide;

4-[3-(4-methylphenyl)-2,5-dibromo-fur-4-yl]benzenesulfonamide;

4-[3-(4-methylphenyl)-2-bromo-fur-4-yl]benzenesulfonamide;

4-[4-(2-methyl-4-fluorophenyl)-fur-3-yl]benzenesulfonamide;

4-[4-(2-fluoropyridin-5-yl)-fur-3-yl]benzenesulfonamide;

4-[4-(2-methylpyridin-5-yl)-fur-3-yl]benzenesulfonamide;

4-[4-(2-chloropyridin-5-yl)-fur-3-yl]benzenesulfonamide;

4-[4-(pyridin-5-yl)-fur-3-yl]benzenesulfonamide;

4-[4-(2-methoxypyridin-5-yl)-fur-3-yl]benzenesulfonamide;

4-[4-(2-fluoropyridin-5-yl)-2,5-dibromo-fur-3-yl]benzenesulfonamide; and

4-[4-(2-fluoropyridin-5-yl)-2-bromofur-3-yl]benzenesulfonamide.

Within Formula I there is a subclass of compounds of high interestrepresented by Formula II:

wherein Y is selected from O, S and NR¹;

wherein R¹ is selected from hydrido and lower alkyl;

wherein X¹ and X² are independently selected from hydrido, halo, loweralkoxycarbonyl and carboxyl;

wherein R² is selected from aryl and heteroaryl; wherein R² isoptionally substituted at a substitutable position with a radicalselected from halo, lower alkoxy and lower alkyl; and

wherein R³⁰ is selected from amino and lower alkyl;

or a pharmaceutically-acceptable salt thereof.

A preferred class of compounds consists of those compounds of Formula IIwherein Y is O or S;

wherein R² is selected from phenyl, naphthyl, biphenyl and pyridyl;wherein R² is optionally substituted at a substitutable position with aradical selected from halo, lower alkoxy and lower alkyl; and

wherein R³⁰ is selected from amino and C₁-C₃ alkyl;

or a pharmaceutically-acceptable salt thereof.

A class of compounds of particular interest consists of those compoundsof Formula II wherein X¹ and X² are independently selected from hydrido,fluoro, chloro, bromo, iodo, methoxycarbonyl, ethoxycarbonyl andcarboxyl;

wherein R² is phenyl or pyridyl; wherein R² is optionally substituted ata substitutable position with a radical selected from fluoro, chloro,bromo, iodo, methoxy, ethoxy, methyl and ethyl; and

wherein R³⁰ is amino or methyl;

or a pharmaceutically-acceptable salt thereof;

A family of specific compounds of particular interest within Formula IIconsists of compounds and pharmaceutically-acceptable salts thereof asfollows:

4-(4-methylsulfonylphenyl)-3-(4-fluorophenyl) thiophene;

4-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)-2,5-dibromothiophene;

4-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)-2-dibromothiophene;

ethyl [3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)thien-2-yl]carboxylate;

2-ethoxycarbonyl-4-(4-methylsulfonylphenyl)-3-(4-methylsulfonylphenyl)thienyl-5-carboxylic acid;

4-(4-fluorophenyl)-3-(4-methylsulfonylphenyl) thienyl-2,5-dicarboxylicacid;

4-(4-methylsulfonylphenyl)-3-(4-methoxyphenyl) thiophene;

4-(4-methylsulfonylphenyl)-3-(4-methoxyphenyl)-2-bromothiophene;

3-(4-methylsulfonylphenyl)-4-phenyl-thiophene;

3-(4-methylsulfonylphenyl)-4-(4-methoxyphenyl) thiophene;

3-(4-methylsulfonylphenyl)-4-(2-methyl-4-fluorophenyl) thiophene;

2-fluror-5-[3-(4-methylsulfonylphenyl) thien-4-yl]pyridine;

4-[4-(4-fluorophenyl) thien-3-yl]benzenesulfonamide;

4-[3-(4-fluorophenyl)-2,5-dibromo-thien-4-yl]benzenesulfonamide;

4-[3-(4-fluorophenyl)-2-bromo-thien-4-yl]benzenesulfonamide; and

3-(4-flurorphenyl)-4-(emthylsulfonylphenyl) furan.

Where the term “alkyl” is used, either alone or within other terms suchas “haloalkyl”, “alkylamine” and “alkylsulfonyl”, it embraces linear orbranched radicals having one to about twenty carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkylradicals are “lower alkyl” radicals having one to about ten carbonatoms. Most preferred are lower alkyl radicals having one to about sixcarbon atoms. Examples of such radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tart-butyl, pentyl, iso-amyl,hexyl, octyl and the like. Where the term “alkenyl” is used, it embraceslinear or branched radicals having two to about twenty carbon atoms or,preferably, two to about twelve carbon atoms. More preferred alkenylradicals are “lower alkyl” radicals having two to about six carbonatoms. Suitable “lower alkenyl” may be a straight or branched one suchas vinyl, allyl, isopropenyl, propenyl, butenyl, pentenyl or the like inwhich preferably one is iospropenyl. Said lower alkeny amy besubstituted with cyano. The term “hydrido” denotes a single hydrogenatom (H). This hydrido radical may be attached, for example, to anoxygen atom to form a hydroxyl radical or two hydrido radicals may beattached to a carbon atom to form a emthylene (—CH₂—) radical. The term“halo” means halogens such as fluorine, chlorine, bromine or iodineatoms. The terms “halo lower alkyl” and “lower alkyl substituted withhalo” embraces radicals wherein any one or more of the alkyl carbonatoms is substituted with halo as defined above. Specifically embracedare monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. Amonohaloalkyl raidcal, for one example, may have either a bromo, chloroor a fluoro atom within the radical. Dihalo radicals may have two ormore of the same halo atoms or a combination of different halo radicalsand polyhaloalkyl radicals may have more than two of the same halo atomsor a combination of different halo radicals. The terms “hydroxyalkyl”and “lower alkyl substituted with hydroxyl” embraces linear or branchedalkyl radicals having one to about ten carbon atoms any one of which maybe substituted with one or more hydroxyl radicals. The terms “loweralkoxy” and “lower alkoxyalkyl” embrace linear or branchedoxy-containing radicals each having alkyl portions of one to about sixcarbon atoms, such as methoxy radical. The term “lower alkoxyalkyl” alsoembraces alkyl radicals having two or more alkoxy radicals attached tothe alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkylradicals. The “lower alkoxy” or “lower alkoxyalkyl” radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” or “haloalkoxyalkyl” radicals.Examples of “alkoxy” radicals include methoxy, ethoxy, propoxy,isopropoxy, in combination, means a carbocyclic aromatic systemcontaining one, two or three rings wherein such rings may be attachedtogether in a pendent manner or may be fused. The term “aryl” embracesaromatic radicals such as phenyl, naphthyl, phenyl substituted withlower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl, di(tert-butyl)phenyl,etc.] and the like, in which the preferable one is phenylnaphthyl,tetrahydronaphthyl, indane and biphenyl. The term “heterocyclic”embraces saturated, partically saturated and unsaturatedheteroatom-containing ring-shaped radicals, where the heteroatoms may beselected from nitrogen, sulfur and oxygen. Examples of saturatedheterocyclic radicals include saturated 3 to 6-membered heteromonocylicgroup containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl,imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms [e.g., thiazolidinyl, etc.]. The term “heteroaryl”embraces unsaturated heterocyclic radicals. Examples of unsaturatedheterocyclic radicals, also termed “heteroaryl” radicals includeunsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.]tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturatedcondensed heterocyclic group containing 1 to 5 nitrogen atoms, forexample, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quniolyl,isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinly [e.g.,tetrazolo [1,5-b]pyridazinly, etc.], etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3- to 6-membered hetermonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example,oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensedheterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogenatoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 3 to6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1to 3 nitrogen atoms, for example, thiazolyl, thiadizaolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.;unsaturated condensed heterocyclic group containing 1 to 2 sulfur atomsand 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl,etc.] and the like. The term also embraces radicals where heterocyclicradicals are fused with aryl radicals. Examples of such fused bicyclicradicals include benzofuran, benzothiphene, and the like. Said“heterocyclic group” may have 1 to 3 substituents such as lower alkyl asexemplified above, hydroxy, oxo, amino and lower alkylamino. Preferablyone is lower alkyl substituted with a heterocyclic group for R¹ ispyrrolidinylmethyl. Preferable one in a heterocyclic group optionallysubstituted with substitutent(s) selected from the group consisting ofhydroxy, oxo, amino and lower alkylamino for R¹ if4-hydroxy-2,5-dioxo-3-pyrrolin-3-yl, 2-aminothiazol-4-yl or2-methylaminothizol-4-yl. The term “sulfonyl”, whether used alone orlinked to other terms such as alkylsulfonyl, denotes respectivelydivalent radicals —SO₂—. “Alkylsulfonyl”, embraces alkyl radicalsattached to a sulfonyl radical, where alkyl is defined as above. Theterm “arylsulfonyl” embraces sulfonyl radicals substituted with an arylradical. The terms “sulfamyl”, “sulfamoyl” or “sulfonamidyl” denote asulfonyl radical substituted with an amine radical, forming asulfonamide (—SO₂NH₂). Suitable “sulfamoyl substituted with lower alkyl”may be methylsulfamoyl, ethylsulfamoyl, isopropylsulfamoyl,dimethylsulfamoyl, diemethylsulfamoyl and the like, in which preferablyone is methylsulfamoyl or dimethylsulfamoyl. The term “acyl”, whetherused alone, or within a term such as “acylamino”, denotes a radicalprovided by the residue after removal of hydroxyl from an organic acid.Suitable “acyl” and acyl moiety in the terms “acylamino” and “loweralkyl(acyl)amino” may be carboxy; esterified carboxy; carbamoyloptionally substituted with substituent(s) selected from the groupconsisting of lower alkyl, halo(lower) alkyl, aryl, hydroxy, loweralkylamino(lower) alkyl, a heterocyclic group (esterified carboxy)loweralkyl and carboxy(lower)alkyl [e.g. lower alkyl-carbamoyl;aryl-carbamoyl; carbamoyl substituted with a heterocyclic group,(esterified carboxy) lower alkyl or carboxy(lower)alkyl; loweralkylcarbamoyl substituted with hydroxy, lower alkylamino, (esterifiedcarboxy)lower alkyl or carboxy(lower)alkyl; etc.]; lower alkanoyl;aroyl; a heterocycliocarbonyl and the like. The term “acylamino”embraces an amino radical substituted with an acyl group. An examples ofan “acylamino” radical is acetylamino (CH₃C(=O)—NH—). The terms“carboxy” or “carboxyl”, whether used alone or with other terms, such as“carboxyalkyl”, denotes —CO₂H. The term “carboxyalkyl” embraces radicalshaving a carboxy radical as defined above, attached to an alkyl radical.The term “carbonyl”, whether used alone or with other terms, such as“alkoxycarbonyl”, denotes —(C=O)—. The term “alkoxycarbonyl” means aradical containing an alkoxy radical, as defined above, attached via anoxygen atom to a carbonyl (C=O) radical. Examples of such“alkoxycarbonyl” ester radicals include (CH₃)₃CO−C(=O)— and —(O=)C−OCH₃.The terms “alkoxycarbonylalkyl” and “esterified carboxylower alkyl”embraces radicals having “alkoxycarbonyl”, as defined above substitutedto an alkyl radical. Examples of such esterified carboxy may besubstituted or unsubstituted lower alkoxycarbonyl [e.g. methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl,2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.], substitutedor unsubstituted aryloxycarbonyl [e.g. phenoxycarbonyl,4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc.], substituted orunsubstituted ar(lower)alkoxycarbonyl [e.g. benzhydryloxycarbonyl,4-nitrobenzyloxycarbonyl, etc.] and the like. The lower alkyl-carbomylmay be substituted with halo or an unsubstituted one such asmethylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl,2,2,2-trifluoroethylcarbamoyl or the like. The aryl-carbamoyl may bephenylcarbamoyl, naphthylcarbamoyl, tolylcarbamoyl, xylylcarbamoyl,mesitylcarbamoyl, cumenylcarbamoyl, and the like, in which thepreferable one is phenylcarbamoyl. The carbamoyl substituted with aheterocyclic group may be one substituted with a heterocyclic group asmentioned above, in which preferably one is tetrazolylcarbamoyl. Thecarbamoyl substituted with (esterified carboxy) lower alkyl may bemethoxycarbonylmethylcarbamoyl, methoxycarbonylethylcarbamoyl,ethoxycarbonylmethyl-carbamoyl, ethoxycarbonylethylcarbamoyl,benzyloxycarbonylmethylcarbamoyl and the like. The carbamoyl substitutedwith carboxy(lower)alkyl may be carboxymethylcarbamoyl,carboxyethylcarbamoyl and the like. The lower alkycarbamoyl substitutedwith hydroxyl may be N-hydroxy-N-methylcarbamoyl,N-ethyl-N-hydroxycarbamoyl, N-hydroxy-N-propylcarbamoyl,N-hydroxy-N-isopropylcarbamoyl and the like, in which the preferable oneis N-hydroxy-N-methylcarbamoyl. The lower alkylcarbamoyl substitutedwith lower alkylamino may be methylaminomethylcarbamoyl,dimethylaminomethylcarbamoyl, dimethylaminoethylcarbamoyl,dimethylaminoethylcarbamoyl, isopropylaminomethylcarbamoyl,isopropylaminoisobutylcarbamoyl and the like, in which the preferableone is dimethylaminoethylcarbamoyl. The lower alkylcarbamoyl substitutedwith (esterfied carboxy) lower alkyl may be(methoxycarbonylmethyl)-ethylcarbamoyl,(ethoxycarbonylmethyl)methylcarbamoyl,(benzyloxcarbonylmethyl)methylcarbamoyl, (benzyloxycarbonylethyl)ethylcarbamoyl and the like, in which preferably one is(ethoxycarbonylmethyl)methylcarbamoyl. The lower alkylcarbamoylsubstituted with carboxy(lower)alkyl may be(carboxymethyl)ethylcarbamoyl, (carboxyethyl)ethylcarbamoyl and thelike, in which the preferable one is (carboxymethyl)methylcarbamoyl. Thelower alkanoyl may be a substituted or unsubstituted one such as formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,hexanoyl, trifluoroacetyl or the like, in which the preferable one isformyl, acetyl, propionyl or trifluoroacetyl. The arcyl may be benzoyl,naphthoyl, toluoyl, di(tert-butyl)benzoyl and the like and the aryl insaid aroyl may be substituted with hydroxyl. The heterocyclic moiety inthe term “a heterocycliccarbonyl” may be one mentioned above as aheterocyclic group and preferably one in said heterocycliccarbonyl ismorpholinocarbonyl, pyrrolidinylcarbonyl or methylpiperazinylcarbonyl.The term “aralkyl” embraces aryl-substituted alkyl radicals such asbenzyl, diphenylmethyl, triphenylmethyl, phenethyl, and diphenethyl. Theterms benzyl and phenylmethyl are interchangeable. The term “alkylthio”embraces radicals containing a linear or branched alkyl radical, of oneto ten carbon atoms, attached to a divalent sulfur atom. An example of“alkylthio” is methylthio, (CH₃—S—). The term “alkylsulfinyl” embracesradicals containing a linear or branched alkyl radical, of one to tencarbon atoms, atached to a divalent —S(=O)— atom. The terms“N-alkylamino” and “N,N-dialkylamino” denote amino groups which havebeen substituted with one alkyl radical and with two alkyl radicals,respectively. Suitable “lower alkylamino” may be mono or di(loweralkyl)amino such as methylamino, ethylamino, dimethylamino, diethylaminoor the like. The term “imino” in “hydroxyimino” and “alkoxyimino”denotes a —C=N— radical. The term “hydroxyimino” denotes a —C=N−OHradical. The term “amide” denotes a radical formed by an aminosubstituted carbonyl, or —C(=O)—NH₂.

The present invention comprises a pharmaceutical composition comprisinga therapeutically-effective amount of a compound of Formula I as definedabove but without excluding compounds defined in the overall provisothat R² and R³ are not at same time 1) para-hydroxyphenyl, 2)para-methoxyphenyl, 3) para-acetoxyphenyl, 4) para-chlorophenyl, 5)para-methylphenyl or 6) para-bromophenyl, but preferably of Formula I,in association with at least one pharmaceutically-acceptable carrier,adjuvant or diluent.

The present invention also comprises a method of treating inflammationor inflammation-related disorders in a subject, the method comprisingadministering to a subject having such inflammation or disorder, atherapeutically-effecitive amount of a compound of Formula I, as definedabove but without excluding compounds defined in the overall provisothat R² and R³ are not at same time 1) para-hydroxyphenyl, 2)para-methoxyphenyl, 3) para-acetoxyphenyl, 4) para-chlorophenyl, 5)para-methylphenyl or 6) para-bromophenyl, but preferably of Formula I inunit dosage form.

Also included in the family of compounds of Formula I are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salts is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phsophoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic,salicyclic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethane-sulfonic, benzenesulfonic, pantothenic,2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, algenic, 3-hydroxybutyric, salicyclic,galactaric and galacturonic acid. Suitable pharmaceutically-acceptablebase addition salts of compouds of Formula I include metallic salts madefrom aluminum, calcium, lithium, magnesium, potassium, sodium and zincor organic salts made from N,N′-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine)and procaine. All of these salts may be prepared by conventional meansfrom the corresponding compound of Formula I by reacting, for example,the appropriate acid or base with the compound of Formula I.

GENERAL SYNTHETIC PROCEDURES

The compound of the invention can be synthesized according to thefollowing procedures of Schemes I-KIII, wherein the R¹-R³ substituentsare as defined for Formula I, above, except where further noted.

Synthetic Scheme I shows the preparation of dialkylester 2 from startingester 1 or diacid 3 where R is lower alkyl. The dialkylester 2 can beprepared by the condensation of alkyl chloroacetate 1 with sodiumsulfide nonahydrate, where Y is sulfur. Alternatively, dialkylester 2can be formed by alcohol esterification of diacid 3.

Synthetic Scheme II show the preparation of diones 7 in three steps fromcommercially available aldehydes. In Step 1, treatment withtrimethylsilyl cyanide (TMSCN) provides the trimethylsiloxy nitrile 5.In Step 2, the nitrile 5 is treated with a Grignard reagent to form thehydroxy ketone 6. In Step 3, the hydroxy ketone 6 is oxidized to givethe desired diketone 7.

Synthetic Scheme III shows the preparation of half ester 8, monoester 9,diacid 10 and 3,4-substituted heterocycles 11 of the present invention.In Step 1, the half ester 8 is formed by the Hinsberg condensation ofdialkyl ester 2 and diketone 7, prepared in Synthetic Schemes I -II,respectively, by treatment with base, such as sodium methoxide orpotassium tert-butoxide, in solvents, such as THF or alcohol. The halfester 8 can be isolated, or saponified in Step 2 to the yield diacid 10.See D. J. Chadwick et al, J. Chem. Soc. Perkin I, 2070 (1972).Alternatively, a procedure analogous to that described in Overberger etal, J. Amer. Chem. Soc., 72, 4958 (1950), can be used to prepare thediacid 10. In step 3, the diacid 10 is carboxylated through the additionof copper powder, quinoline and heat to form the antinflammatory3,4-substituted heterocycle 11 in a process essentially analogous tothat described in D. J. Chadwick et al, J. Chem. Soc. Perkin I, 2079(1972). Alternatively, the half ester 8 can be monodecarboxylated to theester 9 by a method similar to that described in Step 3, above.

Synthetic Scheme IV shows the five step preparation of 3,4-substitutedfurans 17 from the nitrile 12. In step 1, reaction of the nitrile 12with an alkyl lithium, such as methyl lithium at −78° C., is followed byacidification to give the ketone 13. In step 2, the ketone 13 isbrominated to yield the bromoketone 14. The step 3, bromoketone 14 iscoupled with an acid to produce the ester 15. In step 4, cyclization ofthe ester 15 by reflux with p-toluenesulfonic acid and triethylamineproducts the furanone 16. In step 5, furanone 16 is reduced with boranedimethylsulfide complex to give the antiinflammatory furans 17 of thepresent invention.

The compounds of the present invention wherein X is bromo or chloro, areprepared by treating the decarboxylation product heterocycle 11 or 17,prepared in Synthetic Scheme III or IV, with Br₂ or Cl₂, respectively.In other words Cl₂ or Br₂ may be used to yield monohalo or dihaloheterocycle 18 as in the above Scheme V.

Compounds of Formula I, wherein Y is NR¹ and X is chloro or bromo, maybe treated with silver fluoride or potassium fluoride to obtain compound20 of Formula I wherein Y is NR¹ and X is fluoro. This preparation shownin Scheme VI is analogous to that described in U.S. Pat. No. 4,652,582.

Compond 21 of Formula I, wherein Y is S and X is H, may be treated intwo steps, first with alkyilithium and then with perchloroyl fluoride,to obtain compound 22 Formula I, wherein X is fluoro, in the manner setforth in the Scheme VII using methods analogous to those set forth inU.S. Pat. No. 4,590,205.

Alternatively, compounds of Formula I, wherein Y is O or S and X ishydrogen, may be treated with N-fluoropyridinium triflate as set forthin the Scheme VIII using methods analogous to those described inTetrahedron Letters, 27, 4465 (1986).

Alternatively, heterocycle 11 may be substituted at the 2 and 5 positionby methods outlined for each of these substituents in their respectivepatent application and/or Patents, i.e. PCT Publication WO 91/19708,U.S. Pat. Nos. 4,590,205, 4,302,461, 4,427,693 and 4,432,974.

Compounds of Formula I wherein R³ is alkylthiophenyl, may be treatedwith m-chloroperoxybenzoic acid (MCPBA) to obtain other compounds ofFormula I, wherein R³ is alkylsulfonylphenyl, in the manner set forth inScheme IX.

Compounds of Formula I wherein R³ is alkylsulfonylphenyl, may be treatedin three steps to obtain other compounds of Formula I, wherein R³ isbenzenesulfonamide, in the manner set forth in Scheme X. In Step 1, thealkylsulfone is treated at −70° C. with n-butyllithium. In step 2,tri-n-butyl borane in THF is added and refluxed overnight. After coolingto room temperature, water, sodium acetate and hydroxylamine-O-sulfonicacid are added to form the sulfonamide

Synthetic Scheme XI shows the two step preparation of 3,4-disubstitutedheterocyclic antiinflammatory agents 11 from 1,2-dibromo-thiophene 29and the available bromides 28 and 31. In step one, halogen-metalinterchange of 28 with n-butyllithium in THF at −78° C. gives the3-lithiocompounds which subsequently react with zinc chloride to givethe corresponding zinc reagents. Negishi coupling [Negishi et al, J.Org. Chem., 42, 1821 (1977)] of the zinc reagents with 29 gives themonocoupled thiophene bromides 30. In step two, this process is repeatedwith bromides 31 to yield the 3,4-disubstituted heterocyclicantiinflammatory agents 11.

Synthetic Scheme XII shows the two step procedure for the preparation of3,4-disubstituted heterocyclic antiinflammatory agents 11 frommonocoupled thiophene bromides 30 (prepared in Synthetic Scheme XI) andsubstituted boronic acids 33 using a sequential coupling procedure whichis similar to the coupling procedure developed by Suzuki, et al., [Syn.Commun., 11, 513 (1981)]. In step one, halogen-metal interchange of thebromides 31 in THF at −78° C. generates the corresponding organolithiumreagents which are reacted with trimethyl borate. Hydrolysis withhydrochloric acid provides the substituted boronic acids 33. In steptwo, the monocoupled bromides 30 (prepared in Synthetic Scheme XI) arecoupled in toluene at reflux in the presence of Pd^(p) catalyst, e.g.,tetrakis(triphenylphosphine)palladium (0), and 2M sodium carbonate, with33 to give the 3,4-disubstituted heterocyclic antiinflammatory agents 11of this invention.

Alternatively, the heterocycles of the present invention, where Y issulfur and R³ is 4-methylsulfonyl, may be prepared essentially as theMcMurray synthesis, as shown in Scheme XIII. In Step 1, thioanisole 34is acetylated with chloroacetyl 35 in the presence of AlCl₃ to form thehaloacetophenone 36. In Step 2, the thioacetylketone 38 is prepared bythe treatment of ketone 37 with potassium thioacetate in ethanol. InStep 3, intermediates 36 and 38 are coupled to form the dione 39 in thepresence of ammonium hydroxide. In Step 4, diol 40 is formed through thetreatment of dione 39 with TiCl₄ and zinc dust. Thiophene 41 is formedin Step 5 by refluxing diol 40 with p-toluenesulfonic acid in toluene.The antiinflammatory (4-methylsulfonylphenyl) thiophenes 42 of theinvention are formed through the oxidation of the alkylthiophenylthiophene 41 with meta-chloroperoxybenzoic acid in dichloromethane.

An alternate procedure utilized in the present invention is essentiallyanalagous to that outlined by H. Wynberg and H. J. Kooreman, J. Am.Chem. Soc., 87, 1739 (1985).

The following examples contain detailed descriptions of the methods ofpreparation of compounds of Formula I-II. These detailed descriptionsfall within the scope, and serve to exemplify the above describedGeneral Synthetic Procedures which form part of the invention. Thesedetailed descriptions are presented for illustrative purposes only andare not intended as a restriction on the scope of the invention. Allparts are by weight and temperatures are in Degrees centigrade unlessotherwise indicated.

EXAMPLE 1

3-(4-Methylsulfonylphenyl)-4-(4-fluorophenyl)thiophene

Step 1: Preparation of dimethyl thiodiglycolate

A 2L, 4-neck round bottom flask equipped with a mechanical stirrer wascharged with thiodiglycolic acid (300.3 g, 2 mol) and methanol (810 ml).Anhydrous HCl was then bubbled through this solution with stirring for0.5 hours. Stirring was continued for an additional 16 hours at 27° C.at which time the methanol was removed by distillation at reducedpressure. The residue was dissolved in diethyl ether and washed withbrine (300 ml), twice with saturated bicarbonate (2×500 ml) and brine(500 ml). The diethyl ether was dried with Na₂SO₄ and the solventremoved by distillation at reduced pressure. Vacuum distillation of theresulting residue yielded 229.7 g (1.29 mol, 64%) of dimethylthiodiglycolate; ¹H NMR (CDCl₃) δ 3.37 (s, 4H), 3.72 (s, 6H).

Step 2: Preparation of2-methoxycarbonyl-3-(4′-fluorophenyl)-4-(4′-methylthiophenyl)-thienyl-5-carboxylicacid and2-methoxycarbonyl-3-(4′-methylthiophenyl)-4-(4′-fluorophenyl)-thienyl-5-carboxylicacid.

To a stirred solution of 4-fluoro-4′-methylthio benzil (33.34 g, 122mmol) and dimethyl thiodiglycolate (43.4 g, 244 mmol) from Step 1 intetrahydrofuran (THF) (400 ml) at ambient temperature was added 25%NaOMe in methanol solution (83.7 ml, 366 mmol). This solution wasimmediately warmed to 65° C. and stirred for 2.5 hours. The reactionmixture was cooled to room temperature and poured into 1L of 3M NH₄OHand 1L diethyl ether, shaken, and separated. The aqueous layer wasacidified with concentrated Hcl, saturated with NaCl, and extracted with1L ethyl acetate. The ethyl acetate was dried over Na₂SO₄ andconcentrated in vacuo to provide 73.43 g of crude intermediate as a tansolid. The crude intermediate was recrystallized from ethylacetate/iso-octane to provide 39 g (82%) of2-methoxycarbonyl-3-(4′-fluorophenyl)-4-(4′-methylthiophenyl)-thienyl-5-carboxylicacid as a white crystalline solid.

Step 3: Preparation of3-(4′-methylthiophenyl)-4-(4′-fluorophenyl)-thienyl-2,5-dicarboxylicacid.

To a solution of2-methoxycarbonyl-3-(4′-fluorophenyl)-4-(4′-methylthiophenyl)-thienyl-5-carboxylicacid (39 g, 93.6 mmol) from Step 2 in 450 ml THF was added 1N NaOH (468ml). Enough methanol was added to bring reagents back into solution (˜75ml). The reaction was then heated to reflux for 1.5 hours at which timethe reaction was determined to be complete by HPLC monitoring. Thereaction mixture was washed with diethyl ether (500 ml), acidified withconc. HCl, saturated with NaCl, and extracted twice with 500 ml ethylacetate. The ethyl acetate was dried over MgSO₄ and concentrated invacuo to yield 36.84 g of3-(4′-methylthiophenyl)-4-(4′-fluorophenyl)-thienyl-2,5-dicarboxylicacid.

Step 4: Preparation of3-(4′-methylthiophenyl)-4-(4′-fluorophenyl)thiophene.

The diacid from Step 3 (36.84 g, 94.9 mmol) was suspended in 400 ml offreshly distilled quinoline and heated to 180-200 ° C. in an oil bath atwhich time copper powder (3.6 g) was added in one portion. The reactionwas stirred at 180-200° C. for 3 hours, cooled to 130° C., filteredthrough a medium frit glass funnel then cooled to room temperature. Thequinoline was acidified with 3N HCl and extracted twice with diethylether (400 ml). The diethyl ether was dried and concentrated to provide27.83 g of a dark brown solid. The brown solid was dissolved in aminimum amount of ethyl acetate and passed over silica in hexane. Thesilica was washed with 50% ethyl acetate in hexane until no furtherproduct eluted. The product containing fractions were combined andconcentrated to provide 25.37 g (89%) of3-(4′-methylthiophenyl)-4-(4′-fluorophenyl)-thiophene as a white solid.

Step 5: Preparation of 3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)thiophene.

3-(4′-methylthiophenyl)-4(4′-fluorophenyl) thiophene (21.3 g, 70.9 mmol)from Step 4 was dissolved in 500 ml dichloromethane and cooled to −78°C. To this solution was added 50-60% 3-chloroperoxybenzoic acid (MCPBA)(44.5 g, 142 mmol). The reaction was stirred at −78° C. for 1.5 hours atwhich time the cooling bath was replaced with an ice bath and thereaction stirred at 0° C. until reaction was complete by monitoring withHPLC. The reaction was warmed to room temperature, washed with 1M NaHSO₃solution (500 ml), saturated NaHCO₃ (500 ml) and brine. The reactionsolution was dried over Na₂SO₄ and concentrated in vacuo. This materialwas dissolved in 350 ml dichloromethane and 350 ml absolute ethanol wasadded. The dichloromethane was removed by boiling and the solutioncooled to 10° C. for a few hours.3-(4-Methylsulfonylphenyl)-4-(4-fluorophenyl)-thiophene (16 g) wascollected by filtration on a medium frit funnel. Melting point190.5-191.5° C.

EXAMPLE 2

4-(4-Methylsulfonylphenyl)-3-(4-fluorophenyl)-2-bromothiophene EXAMPLE 3

4-(4-Methylsulfonylphenyl)-3-(4-fluorophenyl)-2,5-dibromothiophine

3-(4-Methylsulfonylphenyl)-4-(4-fluorophenyl)-thiophene (102 mg) wasdissolved in acetic acid (75 ml) and heated to 90° C. Bromine in aceticacid (0.1 M, 3.07 ml) was added in one portion. The reaction was stirredfor 15 minutes at which time the solvent was removed at reducedpressure. The residue was dissolved in a minimum of ethyl acetate andchromatographed on silica, eluting with 2.5% isopropanol in hexaneyielding4-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)-2,5-dibromothiophene (CIMS (M+H):489/491/493) and4-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)-2-bromothiophene (CI MS(M+H):411/413).

EXAMPLE 4

3,4-Bis(4-methoxyphenyl)thiophene

Step 1: Preparation of2-methoxycarbonyl-3,4-bis-(4-methoxyphenyl)-thienyl-5-carboxylic acid.

To a stirred solution of 4,4′-bis(methoxy)benzil (3.03 g, 11.2 mmol) anddimethyl thiodiglycolate (3.56 g, 20 mmol) in THF (20 ml), 25% NaOMe inmethanol solution (7.4 ml, 32.4 mmol) was added at ambient temperature.This solution was immediately warmed to 65° C. and stirred for 2.5hours. The reaction was cooled to room temperature and poured into 2MNH₄OH (100 ml) and 100 ml diethyl ether, shaken and separated. Theaqueous layer was acidified with concentrated HCl, saturated with NaCland extracted with ethyl acetate (100 ml). The ethyl acetate was driedover Na₂SO₄ and concentrated in vacuo to provide 1.72 g (40%) of2-methoxycarbonyl-3,4-bis-(4′-methoxyphenyl)-thienyl-5-carboxylic acidas a white solid. CI MS (M+H):399.

Step 2: Preparation of3,4-bis-(4-methoxyphenyl)-thienyl-2,5-dicarboxylic acid.

To a solution of2-methoxycarbonyl-3,4-bis-(4′-methoxyphenyl)-thienyl-5-carboxylic acid(1.6 g, 4.0 mmol) in THF (100 ml) was added 1N NaOH (8.4 ml). Enoughmethanol was added to bring reagents back into solution (˜10 ml). Thereaction was heated to reflux for 6 hours at which time the reaction wascomplete by HPLC monitoring. The THF and methanol were removed atreduced pressure and the residue dissolved in water (300 ml) and diethylether (300 ml). The aqueous layer was acidified with conc. HCl,saturated with NaCl and extracted twice with 300 ml ethyl acetate. Theethyl acetate layers were dried over MgSO₄ and concentrated in vacuo toyield 1.45 g (94%) of 3,4-bis-(4-methoxyphenyl)-thienyl-2,5-dicarboxylicacid. CI MS (M+H):385.

Step 3: Preparation of 3,4-bis(4-methoxyphenyl)thiophene.

3,4-bis-(4-methoxyphenyl)-thienyl-2,5-dicarboxylic acid (1.3 g, 3.4mmol) was suspended in 50 ml of freshly distilled quinoline and heatedto 180-200° C. in an oil bath at which time copper powder (0.2 g) wasadded in one portion. The reaction was stirred at 180-200° C. for 3hours, cooled to 130° C., filtered through a medium frit glass funneland cooled to room temperature. The quinoline was acidified with 3N HCland extracted twice with diethyl ether (40 ml). The diethyl ether layerwas dried and concentrated to provide a dark brown solid. The brownsolid was dissolved in a minimum amount of ethyl acetate and passed oversilica, eluting with hexane. After removal of the hexane, the productwas crystallized from hot absolute ethanol to yield 0.9 g (90%)3,4-bis(4-methoxyphenyl)thiophene bis(4-methoxyphenyl)thiophene as awhite solid. EI MS (M+H):296.

EXAMPLE 5

Ethyl[4-(4-methylsulfonylphenyl)-3(4-fluorophenyl)thien-2-yl]carboxylate

Step 1: Preparation of2-ethoxycarbonyl-3-(4-fluorophenyl)-4-(4-methylthiophenyl)thiophene.

A mixture of2-ethoxycarbonyl-3-(4-fluorophenyl)-4-(4-methylthiophenyl)-thienyl-5-carboxylicacid and2-carboethoxy-3-(4-methylthiophenyl)-4-(4-fluorophenyl)-thienyl-5-carboxylicacid (714 mg), described in Example 1, was suspended in 75 ml of freshlydistilled quinoline and heated to 180-200° C. in an oil bath at whichtime copper powder (0.2 g) was added in one portion. The reaction wasstirred at 180-200° C. for 3 hours, cooled to 130° C., filtered througha medium frit glass funnel and cooled to room temperature. The quinolinewas acidified with 3N HCl and extracted twice with diethyl ether (40ml). The diethyl ether was dried and concentrated to provide a darkbrown solid. The brown solid was dissolved in a minimum amount of ethylacetate and passed over silica, eluting with hexane followed by 5% ethylacetate in hexane to the yield2-ethoxycarbonyl-3-(4-fluorophenyl)-4-(4-methylthiophenyl)thiophene; CIMS (M+H):373.

Step 2: Preparation of2-ethoxycarbonyl-3-(4-fluorophenyl)-4-(4-methylsulphonylphenyl)thiophene.

2-ethoxycarbonyl-3-(4-fluorophenyl)-4-(4-methylthiophenyl)thiophene fromStep 1 (93.1 mg, 0.35 mmol) was dissolved in 10 ml dichloromethane andcooled to −78° C. To this solution was added 50-60% MCPBA (173 mg, 0.5mmol). The reaction was stirred at −78° C. for 1.5 hours at which timethe cooling bath was replaced with an ice bath and the reaction stirredat 0° C. until the reaction was complete as monitored by HPLC. Thereaction was warmed to room temperature and washed with 1M NaHSO₃solution (10 ml), saturated NaHCO₃ (10 ml) and brine. The solution wasdried over Na₂SO₄ and concentrated in vacuo. This residue was dissolvedin ethyl acetate and chromatographed on silica, eluting with a gradientfrom 1%-4% isopropanol in hexane yielding2-ethoxycarbonyl-3-(4-fluorophenyl)-4-(4-methylsulphonylphenyl)thiopheneas a white solid. ¹H NMR (CDCl₃) δ1.2 p (t, 3h, J=7.0 Hz), 3.0 (s, 3h),4.22 (q, 2h, J=7.0 Hz), 7.0 (m, 2h), 7.11 (m, 2h), 7.23 (d, 2h, J=8.4Hz), 7.6 (s, 1H), 7.8 (d, 2h, J=8.4 Hz).

EXAMPLE 6

3-(4-Methylsulfonylphenyl)-4-(4-methoxyphenyl)thiophene

Step 1: Preparation of 3-thioacetyl-4′-methoxy acetophenone.

Potassium thioacetate (2.28 g, 20 mmol) was added to a solution of2-bromo-4′-methoxy acetophenone (4.58 g, 20 mmol) in absolute ethanol(150 ml). The reaction was stirred at ambient temperature under nitrogenfor 16 hours at which time the white precipitate that had formed wasfiltered and the ethanol removed at reduced pressure. The residue wasdissolved in dichloromethane (250 ml) and washed with water (200 ml),brine (200 ml), dried over Na₂SO₄ and the solvent removed at reducedpressure. The resulting residue was chromatographed on silica with agradient from 10%-35% ethyl acetate in hexane to yield 3.4 g (76%) of2-thioacetyl-4′-methoxy acetophenone, ¹H NMR (CDCl₃) δ 2.36 p (s, 3h),3.84 (s, 3h), 4.33 (s, 2h), 6.9 (d, 2h, J=9.2 Hz), 7.9 (d, 2h, J=9.2Hz).

Step 2: Preparation of diketone

2-Thioacetyl-4′-methoxy acetophenone (449 mg, 2 mmol) and2-chloro-4′-methylthioacetophenone (401 mg, 2 mmol) were dissolved inethanol (20 ml). To this solution was added NH₄OH (20 M, 1 ml) and thereaction was stirred for 16 hours at ambient temperature. The ethanolwas removed at reduced pressure, the residue was dissolved in ethylacetate (50 ml) and washed with 1N HCl (30 ml) and brine (30 ml). Theethyl acetate was dried over Na₂SO₄ and the solvent was removed atreduced pressure. The residue was chromatographed on silica eluting with20% ethyl acetate in hexane to yield the diketone (290 mg, 42%). CI MS(M+H):347.

Step 3: Preparation of Diol

The diketone from Step 2(173 mg) was dissolved in anhydrous THF (10 ml)and cooled to −7° C. To this solution was added TiCl₄ (255.1 μl, 2.3mmol) and zinc powder (300 mg). The reaction was stirred at ambienttemperature for 3 hours at which time 10% aq K₂CO₃ (20 ml) anddichloromethane (20 ml) were added and the entire reaction pouredthrough celite. The aqueous and organic layers were separated. Theorganics were washed with water (20 ml), dried over Na₂SO₄ and thesolvent removed at reduced pressure. The residue was chromatographed onsilica, eluting with a gradient from 10%-30% ethyl acetate in hexane toyield 75 mg (31%) of diol. CI MS (M+H):349.

Step 4: Preparation of3-(4-methylthiophenyl)-4-(4-methoxyphenyl)thiophene.

Diol from Step 3 (65 mg) and p-toluenesulphonic acid (15 mg) weredissolved in toluene (10 ml) and heated to reflux under nitrogen for 1hour. The solution was cooled and filtered and diethyl ether (50 ml)added. The organics were washed twice with saturated NaHCO₃ (2×50 ml),once with brine (50 ml), dried over Na₂SO₄ and the solvent removed atreduced pressure. The residual oil was dissolved in a minimum amount ofethyl acetate and chromatographed on silica, eluting with 2% ethylacetate in hexane to yield3-(4-methylthiophenyl)-4-(4-methoxyphenyl)thiophene (53 mg, 95%). EI MS(M+H):312.

Step 5: Preparation of 3-(4-methylsulphonylphenyl)-4-(4-methoxyphenyl)thiophene.

3-(4-Methylthiophenyl)-4(4-methoxyphenyl) thiophene from Step 4 (36.5mg, 0.12 mmol) was dissolved in dichloromethane (10 ml). To thissolution was added 3-chloroperoxybenzoic acid (MCPBA) (88.7 mg of 50%MCPBA) and the reaction stirred under nitrogen for 6 hours. Once thereaction was complete, dichloromethane (25 ml) was added and thereaction washed with Na₂S₂O₅ in water (1g in 25 ml), saturated NaHCO₃(2×25 ml), brine (25 ml), dried over Na₂SO₄ and the solvent removed atreduced pressure. The crude solid was purified by crystallization fromdichloromethane and isooctane to yield3-(4-methylsulphonylphenyl)-4-(4-methoxyphenyl)thiophene (40 mg, 98%).CI MS (M+H):344.

EXAMPLE 7

3-(4-Methylsulfonylphenyl)-4-(4-methoxyphenyl)-5-bromothiophene

3-(4-methylsulphonylphenyl)-4-(4-methoxyphenyl) thiophene from Example 6(9.3 mg) was dissolved in acetic acid (10 ml) and heated to 90° C. atwhich time Br₂ in acetic acid (1.0 M, 27 μl) was added in one portion.The reaction was stirred for 15 minutes at which time the solvent wasremoved at reduced pressure. The residue was dissolved in a minimum ofethyl acetate and chromatographed on silica, eluting with 2.5%isopropanol in hexane, yielding3-(4-methylsulfonylphenyl)-4-(4-methoxyphenyl)-5-bromothiophene. CI MS(M+H):423/425.

EXAMPLE 8

2-Ethoxycarbonyl-4-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)-thienyl-5-carboxylicacid

Step 1. Preparation of 1-(4′-thiomethylphenyl)-1-(trimethylsiloxy)acetonitrile.

A 1L 3-necked round-bottomed flask equipped with magnetic stirrer,nitrogen inlet, reflux condenser, constant pressure addition funnel andthermometer was charged with 4′-methylthiobenzaldehyde (33.5 ml, 0.252mol) and 300 ml of dichloromethane. The addition funnel was charged withtrimethylsilylcyanide (25.0 g, 0.252 mol) dissolved in 100 mldichloromethane. The stirrer was started and approximately 10 ml of thetrimethylsilyl cyanide solution was added from the addition funnel. Asno exotherm was noted, zinc iodide (0.50 g, 0.0016 mol) was added to thereaction. An exotherm of approximately 3° C. was noted, and the additionof the trimethylsilylcyanide solution was continued over about 0.75hour. During the addition, the exotherm produced warmed the reaction toreflux. The reaction was stirred for one hour, during which time itcooled to room temperature, and the mixture was poured into a separatoryfunnel charged with water (300 ml). The layers were separated, and thewater layer was extracted once with dichloromethane (200 ml). Thecombined organic layers were washed with brine (200 ml), dried overanhydrous MgSO4, filtered, and concentrated in vacuo to yield a lightorange oil (61.05 G, 96%), which crystallized upon standing, of1-(4′-thiomethylphenyl)-1-(trimethylsiloxy) acetonitrile, ¹H NMR(CDCl₃/300 MHz) δ7.42 (m, 4H), 5.49 (s, 1H), 2.53 (s, 3H), 0.26 (s, 9H).

Step 2. Preparation of2-(4-thiomethylphenyl)-2-hydroxy-4′-fluoroacetophenone.

An oven-dried, 1L four-necked round-bottomed flask equipped withmechanical stirrer, reflux condenser, nitrogen inlet, constant pressureaddition funnel and thermometer was charged with magnesium turnings(3.31 g, 0.136 mol) and anhydrous THF (200 ml). The addition funnel wascharged with 4-bromo-1-fluorobenzene (15.1 ml, 0.136 mol) dissolved inanhydrous THF (100 ml). Approximately 5 ml of the4-bromo-1-fluorobenzene solution was added to the reaction flask, and animmediate exotherm of 2° C. was observed. The remaining4-bromo-1-fluorobenzene solution was added over ca. 0.75 hour. Duringthe addition, the exotherm produced warmed the reaction to reflux. Uponcomplete addition, the reaction was stirred without temperature controlfor ca. 0.75 hour then cooled to 11° C. The addition funnel was chargedwith 1-(4-thiomethylphenyl)-1-(trimethylsiloxy)-acetophenone (61.05 G,0.242 mol) dissolved in anhydrous tetrahydrofuran (200 ml). Thissolution was added over ca. 0.5 hour, while the reaction temperature wasmaintained lower than 18° C. During the addition, a thick brown oilprecipitated, but was kept in suspension by mechanical stirring. Thereaction was stirred without temperature control for one hour andquenched by addition of 3 N HCl (300 ml). After stirring for one hour,the solution was transferred to a separatory funnel and extracted withethyl acetate (2×300 ml). The combined organic solution was dried overanhydrous MgSO4, filtered, and concentrated in vacuo to yield a darkoil. The oil was dissolved in a minimum amount of boiling ethyl acetate,and isooctane was added until the solution turned cloudy. Upon cooling,tan crystals separated. The suspension was cooled to 0° C., held for 0.5hour, filtered and washed with hexane to provide, after air-drying,2-(4-thiomethylphenyl)-2-hydroxy-4′-fluoroacetophenone (16.6 g, 53%). ¹HNMR (CDCl₃/300 MHz) δ7.93 (m, 2H), 7.20 (m, 4H), 7.06 (m, 2H), 5.86 (s,1H), 2.43 (s, 3H); ¹⁹F NMR (CDCl₃/282.2 MHz) −103.036(t, J=6.77 Hz).

Step 3. Preparation of 4-fluoro-4′-thiomethylbenzil.

A 500 ml three-necked round-bottomed flask equipped with refluxcondenser, thermometer and provisions for magnetic stirring was chargedwith 2-(4-thiomethylphenyl)-2-hydroxy-4′-fluoroacetophenone from Step 2(15.0 g, 54.48 mmol) and 200 ml of glacial acetic acid. The solution waswarmed to ca. 90° C., when Bi₂O₃ (10.16 g, 21.79 mmol) was added. Thesuspension was stirred at reflux for 16 hours, cooled to roomtemperature. The insoluble inorganics were filtered onto a pad of Celiteand washed with glacial acetic acid (50 ml). Water (700 ml) was added,and the resulting suspension was cooled to ca. 15° C. held for 0.5 hour,filtered , washed with water and dried to yield4-fluoro-4′-thiomethylbenzyl (11.98 g, 80%) as a dark yellow solid. ¹HNMR (CDCl₃/300 MHz) δ8.01 (m, 2H), 7.86(m, 2H), 7.29(m, 2H), 7.18(m,3H), 2.53(s, 3H)); ¹⁹F NMR (CDCl₃/282.2 MHz −101.53(m).

Step 4. Preparation of 4-fluoro-4′-methanesulfonylbensil.

A 500 ml one-neck round-bottom flask equipped for magnetic stirring wascharged with 4-fluoro-4′-thiomethylbenzil from Step 3 (10.0 g, 36.46mmol) and dichloromethane (200 ml) and cooled to 0° C.m-Chloroperbenzoic acid (26.42 G, 50 W %, 153.1 mmol) was added, and thesuspension was stirred without temperature control for 16 hours. Thereaction was poured into aqueous Na₂S₂O₅ (5%, 200 ml), and thedichloromethane was evaporated in vacuo. The residue was dissolved inethyl acetate (200 ml) and washed with 5% Na₂S₂O₅ (2×200 ml) andsaturated NaHCO₃ (2×200 ml), dried over anhydrous MgSO₄, filtered andthe solvent evaporated in vacuo to yield4-fluoro-4′-methyslulfonylbenzil (10.8 g, 96%) as a white solid. ¹H NMR(CDCl₃/300 MHz) δ 8.10 (m, 6H), 7.12(m, 2H). 3.08(s, 3H)); ¹⁹F NMR(CDCl₃/282.2 MHz −100.21(m).

Step 5. Preparation of5-ethoxycarbonyl-4-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)-thienyl-2-carboxylicacid and2-ethoxycarbonyl-4-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)-thienyl-5-carboxylicacid.

A 500 ml three-neck round-bottom flask equipped with a reflux condenser,thermometer and provisions for magnetic stirring was charged with4-fluoro-4′-methanesulfonylbenzil from Step 4 (2.5 g, 8.16 mmol) anddiethyl thiodiglycelate (3.03 g, 14.69 mmol) dissolved intetrahydrofuran (200 ml). Sodium ethoxide in ethanol (9.4 ml; 21 W %,23.9 mmol) was added, and the reaction was warmed as reflux. After 1.5hour, the reaction was cooled to room temperature and acidified with 1NHCl (100 ml). The organic solvents were evaporated in vacuo, and theaqueous residue was extracted with diethyl ether (2×200 ml). Thecombined organic solution was washed with 10% NH₄OH solution (3×100 ml).The combined basic aqueous solution was then acidified with conc. HCl topH 2. The resulting suspension of oil in water was extracted withdichloromethane (3×100 ml). The combined organic solution was dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo to anoil. Crystallization from hot ethanol/water yielded, upon drying,yielded5-ethoxycarbonyl-4(4-fluorophenyl)-3-(4-methanesulfonylphenyl)-thienyl-2-carboxylicacid and2-ethoxycarbonyl-4-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)-thienyl-5-carboxylicacid as a 50:50 mix of ester regioisomers (2.38 g, 65%) as a light tansolid 1H NMR (CDCl₃/300 MHz δ 7.78(m, 2H), 7.21(m, 2H), 6.93(m, 4H)4.22(m, 2H) 3.05(s, 3H) 1.22(m, 3H); ¹⁹F NMR (CDCl₃/282.2 MHz) −112.93(m), −113.22 (m). Mass spectrum (M+H): 449.

EXAMPLE 9

4-(4-Fluorophenyl)-3-(4-methanesulfonylphenyl)-thienyl-2,5-dicarboxylicacid

The acidic mother liquor of Example 8, step 5, was concentrated in vacuoto approximately one-third of its original volume (180 ml). Theresulting suspension was cooled to 0° C., held for thirty minutes,drying,4-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)thiophene-2,5-dicarboxylicacid (0.60 g; 17.5%) as a white solid. ¹H NMR (CLCl₃/300 MHz) δ 8.13(m,2H) 8.04(mm 2H), 7.64(m, 2H), 7.47 (m, 2H.

EXAMPLE 10

3-(4-Methanesulfonylphenyl)-4-phenyl-thiophene

A 100 ml one-neck round-bottom flask, equipped with provisions formagnetic stirring, was charged with aqueous ethanol (5 mL) and3-(thiomethylphenyl)-4-phenyl-thiophene (9 mg, 0.032 mmol), preparedaccording to procedures similar to that exemplified in Example 1, withthe substitution of the appropriated substituted benzil(4′-thiomethylbenzil) in Step 3. Oxone (58 mg, 0.096 mmol) was added,and the suspension was stirred at room temperature for 16 hours. Water(75 mL) was added, and the product precipitated. The suspension wascooled to 0° C. and held for one hour. The product was filtered, washedwith water (5 mL), and dried to yield3-(methanesulfonylphenyl)-4-phenyl-thiophene (4.1 mg, 41%) as a whitesolid. ¹H NMR (CDCl₃/300 MHz) δ 7.81(m, 2H), 7.43-7.27(m, 7H), 7.16(m,2H), 3.06 (s, 3H). Mass spectrum (M+H): 314.

EXAMPLE 11

3-(4-Methanesulfonylphenyl)-4-(4-methylphenyl)-thiophene

3-(4-Methanesulfonylphenyl)-4-(4-methylphenyl)thiophene was prepared ina manner similar to that exemplified in Example 10, with thesubstitution of the appropriate substituted benzil(4′-thiomethyl-4-methylbenzil) from Step 3. ¹H NMR (CDCl₃/300 MHz) δ7.81(m, 2H), 7.41-7.31(m, 4H), 7.06(m, 4H), 3.06(s, 3H), 2.35(s, 3H).Mass spectrum (M+H): 329.

EXAMPLE 12

4-[4-(4-Fluorophenyl)thien-3-yl]benzenesulfonamide

To a solution of 3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)thiophene(0.332 g, 1.0 mmol) in THF (8 mL) at −70° C. under nitrogen was added1.6 M n-butyl lithium in hexane (0.66 mL, 1.05 mmol) slowly, viasyringe, and the mixture stirred at -70° C. for 20 minutes and then atroom temperature (25° C.) for 1 hour. After cooling to −70° Cm a 1.0 Msolution of tri-n-butyl borane in THF (1.15 mL, 1.15 mmol) was added andthe mixture allowed to warm slowly to 0° C. for 1 hour, warmed to roomtemperature for 2 hours, and finally stirred at reflux overnight (18hours). After cooling to room temperature and stirring for 3 hours,water (0.8 mL) was added followed by sodium acetate (0.6 g) andhydroxylamine-O-sulfonic acid (0.41 g). After stirring at roomtemperature, overnight, the mixture was poured into 3 volumes of ethylacetate, and the organic layer washed with water and brine and driedover MgSO₄. After solvent removal, the white solids (a mixture ofproduct and starting material) were separated via flash chromatographyon silica gel using a 15% ethyl acetate/85% toluene eluant to yield thebenzenesulfonamide as white solid (59 mg, mp 194-195° C.). Anal. Calc'dfor C₁₆H₁₂NO₂S₂F: C, 57.64; H, 3.63; N, 4.20. Found: C, 57.37; H, 3.69;N, 3.99.

EXAMPLE 13

3-(4-Fluorophenyl)-4-(methylsulfonylphenyl)furan

Step 1: Preparation of 4-(methylthio) acetophenone

To a stirred solution of 4-(methylthio)benzonitrile (50 g, 340 mmol) inTHF (2 L) at −78° C., was added methyllithium (282 ml, 1.4 M in diethylether, 390 mmol) over a period of ten minutes. The solution was stirredat −78° C. for one hour and then the dry ice bath was removed. Afterfive hours 100 ml of water followed by 200 ml of 3N HCl were added tothe reaction mixture and it was stirred overnight. Concentration invacuo gave a residue which was partitioned between ethyl acetate andwater. The water layer was extracted with three portions of ethylacetate and the combined ethyl acetate layers were dried (MgSO₄).Concentration in vacuo gave 58 g of crude 4-(methylthio)acetophenone asa yellow solid: ¹H NMR (CDCl₃) δ 2.52 (s, 3H), 2.57 (s, 3H, 7.62 (d,J=8.7 Hz, 2H), 7.87 (d, H=8.7 Hz, 2H). The sample was used withoutfurther purification.

Step 2: Preparation of 4-(methylsulfonyl) acetophenone.

To a solution of the acetophenone prepared in Step 1 (11.73 g, 71.1mmol) in dichloromethane (500 ml) at ambient temperature was addedm-chloroperoxybenzoic acid (50%, 61.14 g, 177 mmol) in portions over 20minutes. The reaction was stirred for two hours, quenched slowly withsodium metabisulfite, washed with three 100 ml portions of saturatedsodium bicarbonate, dried (MgSO₄), and concentrated in vacuo to give11.91 g (91%) of 4-(methylsulfonyl)acetophenone as an off-white solid:¹H NMR (CDCl₃) δ 2.67 (s, 3H), 3.08 (s, 3H), 8.06 (d, J=9 Hz, 2H), 8.14(d, J=9 Hz, 2H).

Step 3: Preparation of 2-bromo-4′-(methylsulfonyl)acetophenone.

To a stirred solution of the acetophenone prepared in Step 2 (11.91 g,60.5 mmol) in glacial acetic acid (133 ml) and hydrochloric acid (0.11ml) at ambient temperature, was added a solution of bromine (8.22 g,51.4 mmol) in glacial acetic acid (9.3 ml) over a period of three hours.The reaction mixture was diluted with water (500 ml) and extracted withchloroform. The combined chloroform extracts were dried (MgSO₄) andconcentrated in vacuo to give 15.66 g of crude2-bromo-4′-methylsulfonyl)acetophenone: 1H NMR (CDCl₃) δ3.10 (s, 3H),4.45 (s, 2H), 8.08 (d, J=9 Hz, 2H), 8.17 (d, J=9 Hz, 2H). The sample wasused without further purification.

Step 4: Preparation of 2-(4-methylsulfonylphenacyl)-4-fluorophenylacetate.

The bromo acetophenone prepared in Step 3 (8.9 g, 28.9 mmol) was addedto a stirred solution of 4-fluorophenyl acetic acid (4.45 g, 28.9 mmol)in triethylamine (3.26 g, 31.8 mmol) and acetonitrile (275 ml) atambient temperature and stirred for 30 minutes. The reaction wasconcentrated in vacuo and the residue partitioned between ethyl acetateand water. The organic fraction was dried (MgSO₄) and concentrated invacuo. The residue was purified by silica gel chromatography (40% ethylacetate/hexane) to give 6.87 g (68% yield) of2-(4′-methylsulfonylphenacyl)-4-fluorophenyl acetate as a colorlesssolid: ¹H NMR (CDCl₃) δ 3.08 (s, 3H), 3.79 (s, 2H), 5.35 (s, 2H), 7.06(s, t, J=9 Hz, 2H), 7.32 (q, J=6, 9 Hz, 2H) 8.06 (s, 4H)

Step 5: Preparation of3-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-(5H)-furanone.

The phenylacetate prepared in Step 4 (4.40 g, 11.7 mmol) was combinedwith triethylamine (6.52 ml, 46.8 mmol), p-toluenesulfonic acid (4.89 g,25.7 mmol), and 4Å molecular sieves (12.0 g) in acetonitrile (117 ml)and heated to reflux for 16 hours. The reaction was concentrated invacuo and the residue partitioned between dichloromethane and water. Thedichloromethane fraction was dried (MgSO₄) and concentrated in vacuo.Recrystallization from hexane/ethyl acetate (2:1) gave 3.65 g (94%) of3-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2(5H)-furanone as a solid:mp 166-167° C.; ¹H NMR (CDCl₃) δ 3.08 (s, 3H), 5.19 (s, 2H), 7.10 (t,J=9 Hz, 2H), 7.42 (q, J=6, 9 Hz, 2H), 7.52 (d, J=9 Hz, 2H), 7.97 (d, J=9Hz, 2H); HRMS. Calc'd for M+H: 333.0519. Found 332.0501. Anal. Calc'dfor C₁₇H₁₃FO₄S: C, 61.44; H, 3.94; O 19.36, Found: C, 61.11; H, 4.06; O,19.32.

Step 6: Preparation of3-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)furan

Under nitrogen, borane dimethyl sulfide complex (2M in toluene, 3.6 ml,7.2 mmoles) was added with stirring to the furanone prepared in Step 5(0.6 g, 1.8 mmoles) in 10 ml of THF. After two hours, additional boranedimethyl sulfide complex (2M in toluene, 5.4 ml, 10.8 mmoles) was added.The reaction was stirred at ambient temperature for one hour and at 5°C. for 62 hours. The reaction was concentrated in vacuo and the residueslowly mixed with 50 ml of ice water and extracted with three 25 mlportions of ethyl acetate. The combined organic fractions were washedwith 25 ml brine, dried (MgSO₄), and concentrated in vacuo. Purificationby silica gel chromatography (5% ethyl acetate/dichloromethane) gave0.22 g (38%) of a colorless solid. Recrystallization from ethylacetate/hexane gave 3-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)furan:mp 160-161° C.; ¹H NMR (CDCl₃) δ 3.07 (S, 3H), 6.99-7.07 (M, 2H);7.13-7.21 (m, 2H), 7.37-7.42 (m, 3H), 7.56 (d, J=1.8 Hz, 1H) 7.66 (d,J=1.6 Hz, 1H), 7.83-7.89 (m, 2H); ¹⁹F NMR (CDCl₃) δ −114.80 to −114.90(m): MS m/e (M+H) 317(73), (M+) 316(100); HRMS. Calc'd for M+H;316.0569. Found: 316.0571. Anal. Calc'd for C₁₇H₁₃FO₃S: C, 64.55; H,4.14; F, 6.01; A, 10; 0.13 Found: C, 64. 59; H, 4.02; F, 6.22; S, 10.52.

EXAMPLE 14

3-(4-Methylsulfonylphenyl)-4-(4-fluoropyridin-3-yl) thiophene

Step 1: Preparation of 4-(4 methylthiophenyl)-3-bromothiophine

4-Bromothioanisole (4.197 g, 20.7 mmol.) was dissolved in 50 ml of dryTHF and cooled to −78° C. N-butyllithium (2.5M, 9.1 ml, 22.77 mmol) wasadded via syringe and allowed to stir for 30 minutes. 1.0 M Zinc bromidein THF (24.0 ml) was added and the reaction warmed to room temperature.A solution of the dibromothiophene (1 eq., 20.7 mmol, 5.0 g), 25 ml ofTHF, and tetrakis(triphenylphosphine) palladium(0) (5% 1 mmol.) wasadded via syringe to the zinc-thioanisole solution. The reaction wasstirred at reflux overnight. The reaction mixture was concentrated,dissolved in ethyl acetate, washed with sat. ammonium chloride, followedby sat. brine, dried (MgSO₄), and reconcentrated to give 2.0 g of crudematerial. Purification by silica gel chromatography (Waters LC 2000)with hexane gave 1.0 g (20%) of pure monosubstituted thiophene material.NMR(CDCl₃): δ 2.52(s, 3H), 7.22(d, J=6 Hz, 1H), 7.30(d, J=8 Hz, 2H.

Step 2: Preparation of 4-(4methylthiophenyl)-3-(4-fluorophenyl)thiophene.

The monosubstituted thiophene (1.0 g, 3.5 mmol) from Step 1 wasdissolved in 15 ml of tetrahydrofuran and cooled to −78° C. prior toaddition of n-butyllithium (2.5 M, 1.1 eq, 3.9 mmol., 1.5 ml). Thereaction was stirred for 30 minutes at −78° C., zinc bromide intetrahydrofuran (1.0 M, 1.2 eq, 4.2 mmol.) was added, and the solutionwas allowed to warm to 23° C. a mixture of 2-fluoro-5-bromo-pyridine (3eq, 10.5 mmol, 1.85 g), nickel (+2)(diphenylpalladium) chloride (0.5 eq,100 mg) and tetrahydrofuran (20 ml) was added and the reaction and wasstirred at reflux overnight. The solution was concentrated in vacuo. Theresidue was dissolved in ethyl acetate and washed with water, dried(MgSO₄) and reconcentrated. Purification by silica gel chromatography(Waters, LC-2000) with hexane gave 330 mg (33%) of the desired 4-(4methylthiophenyl-3-(4-fluorophenyl)thiophene as an oil: NMR (CDCl₃): δ2.49(s, 3H), 6.81 (dd, J=2 Hz, J=8 Hz, 1H), 7.08(d, J=8 Hz, 2H), 7.16(d,J=8 Hz, 2H), 7.35(dd, J=2 Hz, J=8 Hz, 2H), 7.49(td, J=2 Hz, J=6 Hz, 1H),8.14(d, J=1Hz, 1H).

Step 3: Preparation of 4-(4 methylsulfonylphenyl)-3-(4-fluorophenyl)thiophene.

The 4-(4 methylthiophenyl)-3-(4-fluorophenyl) thiophene (330 mg, 1.1mmol.) FROM STEP 2 was dissolved in 9.0 ml of dichloromethane, to whichmeta-chloroperbenzoic acid (MCPBA) (2 eq, 2.2 mmol) was added in oneportion. The reaction was stirred for 20 minutes at 23° C. and quenchedwith 500 mg of sodium metabisulfite in 10 ml of water. The organic layerwas diluted with dichloromethane and washed repeatedly with sat. sodiumbicarbonate and sat. brine. The organic layer was dried (MgSO₄) andconcentrated in vacuo. Recrystallization from ethyl acetate/hexane (1:2)gave 266 mg (73%) of 4-(4methylsulfonylphenyl)-3-(4-fluorophenyl)thiophene: mp 190-191° C.(dec)); MMR(CDCl₃) δ 3.09(s, 3H), 6.84-6.90(m, 1H), 7.36(d, J=8 Hz, 2H),7.42(d, J=2 Hz, 1H), 7.45-7.53(m, 2H), 7.88(d, J=7 Hz, 2H), 8.10(bs,1H). Anal. Calc'd for C₁₆H₁₂NFO₂S₂: C, 57.59; H,3.60; N, 4.20; F, 5.67.Found: C, 57.39; H,3.75; N, 3.97; F,5.50.

EXAMPLE 15

3-(4-Mehtylsulfonylphenyl)-4-(2-methyl-4-fluorophenyl) thiophene

Step 1: Preparation of 2-methyl-4-fluorophenyl boronic acid.

2-Bromo-5-fluorotoluene (52.0 mmol, 10 g) in 400 ml of tetrahydrofuranwas cooled to −78° C. and n-butyllithium (2.5 M, 58.2 mmol) was added.The solution was stirred for 20 minutes, trimethoxy borane (3 eq, 0.16mol) was added, and the reaction was allowed to warm to room temperatureovernight. Sodium hydroxide (60 ml of 1.25 M) was added and the reactionwas stirred for 30 minutes. The tetrahydrofuran was removed in vacuo.The remaining aqueous layer was diluted and extracted with diethylether. The aqueous layer was adjusted to pH 3 with 2N HCl and extractedwith ethyl acetate, which was dried (MgSO₄) and concentrated in vacuo togive 6.57 g (81%) of a colorless solid: MS(FAB) m/e (rel. intensity)154(48), 136(100).

Step 2: Preparation of3-(4-methylthiophenyl)-4-(2-methyl-4-fluorophenyl)thiophene.

The mono-substituted thiophene from Example 14 (1.8 mmol, 520 mg) wascombined with the 2-methyl-4-fluorophenyl boronic acid (2 eq, 3.6 mmol,562 mg) in 8.0 ml of toluene, 4.3 ml of 2 M sodium carbonate, 10 ml ofethanol and tetrakis(triphenylphosphine)-palladium(0) (1.0 g) and wasstirred at reflux overnight. The reaction was concentrated in vacuo andthe residue was partitioned between toluene and water. The toluene layerwas dried (MgSO₄) and reconcentrated in vacuo. The residue was purifiedvia silica chromatography (Waters, LC-2000) in 97% hexane/ethyl acetateto give 3-(4-methylthiophenyl)-4-(2-methyl-4-fluorophenyl)thiophene (420mg) as a semi-solid. NMR (CDCl₃) δ 1.90(s, 3H), 2.43(s, 3H), 6.8-6.9(m,2H) 7.05(q, J=8 Hz, 4H), 7.12-7.18(m, 2H), 7.33(d, J≦2 Hz, 1H).

Step 3: Preparation of3-(4-methylsulfonylphenyl)-4-(2-methyl-4-fluorophenyl) thiophene.

3-(4-methylthiophenyl)-4-(2-methyl-4-fluorophenyl)thiophene (420 mg,1.34 mmol) from Step 2 was dissolved in 20 ml of dichloromethane andtreated with meta-chloroperbenzoic acid (2 eq, 2.68 mmol). The reactionwas stirred at room temperature for 20 minutes, diluted withdichloromethane, quenched with sodium metabisulfite (550 mg in 10 mlwater) washed with sat. sodium bicarbonate, dried (MgSO₄) andconcentrated in vacuo. The residue was crystallized from ethylacetate/hexane (1,3) to give3-(4-methylsulfonylphenyl)-4-(2-methyl-4-fluorophenyl)thiophene (200mg): mp 158-160° C.; NMR (CDCl₃): δ 1.8(s, 3H), 3.1(s, 3H), 6.82-6.92(m,2H), 7.12-7.18(m, 1H), 7.22(d, J=2 Hz, 1H), 7.30(d, J=8 Hz, 2H, 7.49(d,J=2 Hz, 1H, 7.77(d, J=8 Hz, 2H); MS(FAB) m/e (rel. intensity) 353(m+Li),(70), 347(40), 220(35). Anal. Calc'd for C₁₈H₁₅FO₃S₂: C,62.45, H, 4.34,F, 5.46. Found: C, 62.14, H, 4.47, F, 5.20.

BIOLOGICAL EVALUATION

Rat Carrageenan Foot Pad Edema Test

The carrageenan foot edema test was performed with materials, reagentsand procedures essentially as described by Winer, it al., (Proc. Soc.Exp. Biol. Med., 111, 544 (1962)). Male Sprague-Dawley rats wereselected in each group so that the average body weight was as close aspossible. Rats were fasted with free access to water for over sixteenhours prior to the test. The rats were dosed orally (1 mL) withcompounds suspended in vehicle containing 0.5% methylcellulose and0.025% surfactant, or with vehicle alone. One hour later a subplantarinjection of 0.1 mL of 1% solution of carrageenan/sterile 0.9% salinewas administered and the volume of the injected foot was measured with adisplacement plethysmometer connected to a pressure transducer with adigital indicator. Three hours after the injection of the carrageenan,the volume of the foot was again measured. The average foot swelling ina group of drug-treated animals was compared with that of a group ofplacebo-treated animals and the percentage inhibition of edema wasdetermined. Otterness and Bliven, Laboratory Models for Testing NSAIDs,in Non-steroidal Anti-Inflammatory Drugs, (J. Lombardino, ed. 1985)).Results are shown in Table I.

Rat Carrageenan-induced Analgesia Test

The analgesia test using rat carrageenan was performed with materials,reagents and procedures essentially as described by Hargreaves, et al.,(Pain, 32, 77 (1988)). Male Sprague-Dawley rats were treated aspreviously described for the Carrageenan foot Pad Edema test. Threehours after the invention of the carrageenan, the rats were placed in aspecial plexiglass container with a transparent floor having a highintensity lamp as a radiant heat source, positionable under the floor.After an initial twenty minute period, thermal stimulation was begun oneither the injected foot or on the contralateral uninjected foot. Aphotoelectric cell turned off the lamp and timer when light wasinterrupted by paw withdrawal. The time until the rat withdraws its footwas then measured. The withdrawal latency in seconds was determined forthe control and drug-treated groups, and percent inhibition of thehyperalgesic foot withdrawal determined. Results are shown in Table I.

TABLE I RAT PAW EDEMA ANALGESIA % Inhibition % Inhibition @ 10 mg/kgbody weight % 20 mg/kg body weight Examples  1  8  2 30  0*  4 22 14 3028 15 20 *@ 3 mpk

Evaluation of COX-I and COX-II activity in vitro

a. Preparation of recombinant COX baculoviruses

A 2.0 kb fragment containing the coding region of either human or murineCOX-I or human or murine COX-II was cloned into a BamHl site of thebaculovirus transfer vector pVL1393 to generate the baculovirus transfervector. Recombinant baculoviruses were isolated by transfecting 4 μg ofbaculoviruses transfer vector DNA into SF9 cells (2×10e8) along with 200ng of linearized baculovirus plasmid DNA by the calcium phosphatemethod. Recombinant viruses were purified by three rounds of plaquepurification and high titer (10E7-10E8 pfu/ml) stocks of virus wereprepared. For large scale production, SF9 insect cells were infected in10 liter fermentors (Bioprocess group) (0.5×10⁶/ml) with the recombinantbaculovirus stock such that the multiplicity of infection was 0.1. After72 hours the cells were centrifuged and the cell pellet homogenized inTris/Sucrose (50 mM: 25%, pH 3.0) containing 1% CHAPS. The homogenatewas centrifuged at 10,000×G for 30 minutes, and the resultantsupernatant was stored at −30° C. before being assayed for COX activity.

b. Assay for COX I and COX II activity:

COX activity was assayed as PGE₂ formed/μg protein/time using an ELISAto detect the prostaglandin released. CHAPS-solubilized insect cellmembranes containing the appropriate COX enzyme were incubated in apotassium phosphate buffer (50 mM, pH 8.0) containing epinephrine,phenol, and heme with the addition of arachidonic acid (10 μm).Compounds were pre-incubated with the enzyme for 10-20 minutes prior tothe addition of arachidonic acid. Any reaction between the arachidonicacid and the enzyme was stopped after ten minutes at 37° C./roomtemperature by transferring 40 μl of reaction mix into 160 μl ELISAbuffer and 25 μM indomethacin. The PGE₂ formed was measured by standardELISA technology (Cayman Chemical). Results are shown in Table II.

TABLE II Murine COX I Murine COX II ID₅₀ μM ID₅₀ μM Examples 1 >100* <.12   3.5 <.1 3  100 1.5 4   .3  .8 5  >3 <.1 6   <.3 <.1 7   <.1 <.18 >100 5.5 9 >100 4.7 10   >10 <.1 11  >100 <.1 13  >100* 1.9 14   >10 .2 15    8.5 <.1 *human COX I and COX II enzymes

Whole Blood Assay for Thromboxane B₂ activity:

Thromboxane B₂ (TXB₂) activity was assayed using an ELISA to detect theTXB₂ released. Various concentrations of compounds and standards wereprepared by a set of serial dilutions (1:3) in a microtiter place withethanol. In U-bottom microtiter plates, 50 μl whole blood *green topheparin), 150μl RPMI media (JRH Biosciences) and 5 μl compound solutionwere mixed and preincubated at 37° C. for fifteen minutes prior to theaddition 4 μg of the calcium ionophore A23187. Any reaction between thecompounds and the cells was stopped after ten minutes at 37° C. bycentrifuging the cells at 2000 rpm for ten minutes at 4° C. andtransferring 20μl of the supernatant into 180μl ELISA enzyme immunoassay buffer. The TXB₂ formed was measured by standard ELISA technology(Cayman Chemical). To washed and pre-coated (goat anti-rabbit IgG H&L)microtiter plates, was added 40 μl enzyme immune assay buffer, 10 μldiluted supernatants, 50 μl TXB₂ tracer and 50 μl TXB₂ antisera. Aftercovered overnight incubation at room temperature, 300 μl Ellman reagentwas added and incubated. The absorbance was read at 405 nm with a 650 nmreference. Results are shown in Table III.

TABLE III Thromboxane B₂ IC₅₀ μM Examples 1 21 2 .4 4 <.1 7 <.1 10  711  7 14  27 15  28

The antiinflammatory agents of this invention can be administered totreat inflammation by any means that produces contact of the activeagent with the agent's site of action in the body of a mammal,preferably human. These agents can be administered by any conventionalmeans available for use in conjunction with pharmaceuticals, either asindividual therapeutic agents or in a combination of therapeutic agents.The agents can be administered alone, but are generally administeredwith a pharmaceutical carrier select on the basis of the chosen route ofadministration, preferably oral, and standard pharmaceutical practice.

The amount of therapeutically active compound that is administered andthe dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention depends on a variety of factors,including the age, weight, sex and medical condition of the subject, theseverity of the disease, the route and frequency of administration, andthe particular compound employed, and thus may vary widely. Thepharmaceutical compositions may contain active ingredient in the rangeof about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mgand most preferably between about 1 and 100 mg. A daily dose of about0.01 to 100 mg/kg body weight, preferably between about 0.1 and about 50mg/kg body weight and most preferably from about 1 to 20 mg/kg bodyweight, may be appropriate. The daily dose can be administered in one tofour doses per day.

The compounds of the present invention may be administered orally,parenterally, by inhalation spray, rectally, or topically in dosage unitformulations containing conventional nontoxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles as desired. Topicaladministration may also involve the use of transdermal administrationsuch as transdermal patches or iontophoresis devices. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or setting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid fine use inthe preparation of injectables.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such aslactose, sucrose, starch powder, cellulose esters of alkanoic acids,cellulose alkyl esters, talc, stearic acid, magnesium oxide, sodium andcalcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andthen tableted or encapsulated for convenient administration. Suchcapsules or tablets may contain a controlled-release formulation as maybe provided in a dispersion of active compound in hydroxypropylmethylcellulose. Such dosage forms may also comprise, as in normal practice,additional substances other than inert diluents, e.g., lubricatingagents such as magnesium stearate. In the case of capsules, tablets, andpills, the dosage forms may also comprise buffering agents. Tablets andpills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents. Pharmaceutically acceptable carriers encompass all theforegoing and the like.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more immunomodulators, antiviral agents or other antiinfectiveagents. For example, the compounds of the invention can be administeredin combination with antihistamines or with other such agents knownheretofore to be effective in combination with antiinflammatory agents.When administered as a combination, the therapeutic agents can beformulated as separate compositions which are given at the same time ordifferent times, or the therapeutic agents can be given as a singlecomposition.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. The active ingredient mayalso be administered by injection as a composition wherein, for example,saline, dextrose or water may be used as a suitable carrier.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations.

What is claimed is:
 1. A compound of Formula I

wherein Y is O; wherein X is one or more substituents selected from a)hydrido, halo, cyano, nitro, hydroxy, acyl, lower alkyl substituted at asubstitutable position with a substituent selected from halo, hydroxyl,amino, acylamino, lower alkylamino, lower alkyl(acyl)amino, acyl, aryloptionally substituted with hydroxyl, a heterocyclic group, hydroxyiminoand lower alkoxyimino, lower alkenyl optionally substituted at asubstitutable position with cyano, amino optionally substituted at asubstitutable position with a radical selected from acyl and loweralkylsulfonyl, sulfo, sulfamoyl optionally substituted with asubstituent selected from the group consisting of lower alkyl,halo(lower)alkyl, aryl, hydroxyl, lower alkylamino(lower)alkyl, aheterocyclic group and (esterified carboxy)lower alkyl, N-containingheterocyclicsulfonyl, a heterocyclic group optionally substituted at asubstitutable position with a substituent selected from the groupconsisting of hydroxyl, oxo, amino and lower alkylamino, b) S(O)_(n)R⁵,wherein R⁵ is C₁-C₆ alkyl optionally substituted at a substitutableposition with fluoro, and n is 0, 1 or 2, c) C(R⁶)(OR⁸)(R⁷) wherein R⁶and R⁷ independently are selected from CF₃, CF₂H, CFCl₂, CF₂Cl, CClFH,CCl₂F, CF₃CF₂ and C₁-C₂ alkyl, and wherein R⁸ is selected from hydrido,C₁-C₄ alkyl, (C₁-C₃ alkyl)C(O) and CO₂R⁹, wherein R⁹ is C₁-C₄ alkyl, d)C(O)ZR⁴, wherein Z is O, N, or S, and R⁴ is selected from hydrido, C₁-C₆alkyl and aryl, and when Z is N then R⁴ is independently taken twice,and e) C(R⁹)(NHR¹¹)(R¹⁰), wherein R⁹ and R¹⁰ are independently selectedfrom CF₃, CF₂H, CF₂Cl, CClFH and CCl₂H, and R¹¹ is selected from hydridoand C₁-C₃ alkyl; and wherein R² and R³ are independently selected fromaryl or heteroaryl, wherein the aryl or heteroaryl radical is optionallysubstituted at a substitutable position with a radical selected fromhalo, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl,lower alkylsulfonyl, nitro, amide, amino, lower alkylamino, sulfamyl andlower alkylsulfonylamino; provided that at least one of R² and R³ issubstituted with lower alkylsulfonyl or sulfamyl; or apharmaceutically-acceptable salt thereof.
 2. A compound of claim 1wherein X is S(O)_(n)R⁵, wherein R⁵ is C₁-C₆ alkyl optionallysubstituted at a substitutable position with fluoro, and n is 0, 1 or 2;or a pharmaceutically-acceptable salt thereof.
 3. A compound of claim 1wherein X is C(R⁶)(OR⁸)(R⁷) wherein R⁶ and R⁷ independently are selectedfrom CF₃, CF₂H, CFCl₂, CF₂Cl, CClFH, CCl₂F, CF₃CF₂ and C₁-C₂ alkyl;wherein R⁸ is selected from hydrido, C₁-C₄ alkyl, (C₁-C₃ alkyl)C(O) andCO₂R⁹; and wherein R⁹ is C₁-C₄ alkyl; or a pharmaceutically-acceptablesalt thereof.
 4. A compound of claim 1 wherein X is C(R⁹)(NHR¹¹)(R¹⁰),wherein R⁹ and R¹⁰ are independently selected from CF₃, CF₂H, CFCl₂,CF₂Cl, CClFH and CCl₂H, and R¹¹ is selected from hydrido and C₁-C₃alkyl; or a pharmaceutically-acceptable salt thereof.
 5. A compound ofclaim 1 wherein R² and R³ are independently selected from aryl andheteroaryl, wherein the aryl or heteroaryl radical is optionallysubstituted at a substitutable position with halo, lower alkyl, loweralkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl,nitro, amino, lower alkylamino, sulfamyl and lower alkylsulfonylamino;or a pharmaceutically-acceptable thereof, provided that at least one ofR² or R³ is substituted with lower alkylsulfonyl or sulfamyl. 6.Compound of claim 1 wherein X is one or two substituents selected fromhydrido, halo, cyano, nitro, hydroxyl, acyl, lower alkyl substituted ata substitutable position with a substituent selected from halo,hydroxyl, amino, acylamino, lower alkylamino, lower alkyl(acyl)amino,acyl, aryl optionally substituted with hydroxyl, a heterocyclic group,hydroxyimino and lower alkoxyimino, lower alkenyl optionally substitutedat a substitutable position with cyano, amino optionally substituted ata substitutable position with a radical selected from acyl and loweralkylsulfonyl, sulfo, sulfamoyl optionally substituted with asubstituent selected from the group consisting of lower alkyl,halo(lower)alkyl, aryl, hydroxyl, lower alkylamino(lower)alkyl, aheterocyclic group and (esterified carboxy)lower alkyl, N-containingheterocyclicsulfonyl, a heterocyclic group optionally substituted at asubstitutable position with a substituent selected from the groupconsisting of hydroxyl, oxo, amino and lower alkylamino; and wherein R²and R³ are independently selected from aryl and heteroaryl, wherein thearyl or heteroaryl radical is optionally substituted at a substitutedposition with a radical selected from halo, lower alkyl, lower alkoxy,lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro, amino,amide, lower alkylamino, sulfamyl and lower alkylsulfonylamino; or apharmaceutically-acceptable salt thereof, provided that at least one ofR² or R³ is substituted with lower alkylsulfonyl or sulfamyl. 7.Compound of claim 1 wherein X is one or two substituents selected fromhydrido, halo, cyano, nitro, hydroxyl, carboxy, lower alkoxycarbonyl,lower alkyl substituted at a substitutable position with a substituentselected from halo, hydroxyl, amino, acylamino, lower alkylamino, loweralkyl(acyl)amino, lower alkoxycarbonyl, carboxy, a heterocyclic group,hydroxyimino and lower alkoxyimino, lower alkenyl optionally substitutedat a substitutable position with cyano, amino optionally substituted ata substitutable position with a radical selected from acyl and loweralkylsulfonyl, sulfo, sulfamoyl optionally substituted with asubstituent selected from the group consisting of lower alkyl,halo(lower)alkyl, aryl, hydroxyl, lower alkylamino(lower)alkyl, aheterocyclic group and (alkoxycarbonyl)lower alkyl, N-containingheterocyclicsulfonyl, a heterocyclic group optionally substituted at asubstitutable position with a substituent selected from the groupconsisting of hydroxyl, oxo, amino and lower alkylamino; and wherein R²and R³ are independently selected from aryl and heteroaryl, wherein thearyl or heteroaryl radical is optionally substituted at a substitutableposition with a radical selected from halo, lower alkyl, lower alkoxy,lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro, amino,amide, lower alkylamino, sulfamyl and lower alkylsulfonylamino; or apharmaceutically-acceptable salt thereof, provided that at least one ofR² or R³ is substituted with lower alkylsulfonyl or sulfamyl.
 8. Acompound of claim 1 wherein X is one or two substituents selected fromhydrido, fluoro, chloro, bromo and iodo; or apharmaceutically-acceptable salt thereof.
 9. A compound of Formula II

wherein Y is O; wherein X¹ and X² are independently selected fromhydrido, halo, lower alkoxycarbonyl and carboxyl; wherein R² is selectedfrom aryl and heteroaryl; wherein R² is optionally substituted at asubstitutable position with a radical selected from halo, lower alkoxyand lower alkyl; and wherein R³⁰ is selected from amino and lower alkyl;or a pharmaceutically-acceptable salt thereof.
 10. Compound of claim 9wherein R² is selected from phenyl, naphthyl, biphenyl, and pyridyl;wherein R² is optionally substituted at a substitutable position with aradical selected from halo, lower alkoxy and lower alkyl; and whereinR³⁰ is selected from halo, lower alkoxy and lower alkyl; and or apharmaceutically-acceptable salt thereof.
 11. Compound of claim 10wherein X¹ and X² are independently selected from hydrido, fluoro,chloro, bromo, iodo, methoxycarbonyl, ethoxycarbonyl and carboxyl;wherein R² is phenyl or pyridyl; wherein R² is optionally substituted ata substitutable position with a radical selected from fluoro, chloro,bromo, iodo, methoxy, ethoxy, methyl and ethyl; and wherein R³⁰ is aminoor methyl; or a pharmaceutically-acceptable salt thereof.
 12. Thecompound of claim 11 and its pharmaceutically-acceptable salts whereinsaid compound comprises:3-(4-fluorophenyl)-4-(methylsulfonylphenyl)furan.
 13. A pharmaceuticalcomposition comprising a therapeutically-effective amount of anantiinflammatory compound, said compound selected from a compound ofclaim 1; or a pharmaceutically-acceptable salt thereof.
 14. Apharmaceutical composition comprising a therapeutically-effective amountof an antiinflammatory compound, said compound selected from a compoundof claim 9; or a pharmaceutically-acceptable salt thereof.
 15. Apharmaceutical composition comprising a therapeutically-effective amountof an antiinflammatory compound, said compound selected from a compoundof claim 10; or a pharmaceutically-acceptable salt thereof.
 16. Apharmaceutical composition comprising a therapeutically-effective amountof an antiinflammatory compound, said compound selected from a compoundof claim 11; or a pharmaceutically-acceptable salt thereof.
 17. Apharmaceutical composition comprising a therapeutically-effective amountof an antiinflammatory compound, said compound selected from a compoundof claim 12; or a pharmaceutically-acceptable salt thereof.
 18. A methodfor treating inflammation or an inflammation-associated disordercomprising administering a therapeutically effective amount of acompound of claim 1 to a subject in need thereof.
 19. A method fortreating inflammation or an inflammation-associated disorder comprisingadministering a therapeutically effective amount of a compound of claim9 to a subject in need thereof.
 20. A method for treating inflammationor an inflammation-associated disorder comprising administering atherapeutically effective amount of a compound of claim 10 to a subjectin need thereof.
 21. A method for treating inflammation or aninflammation-associated disorder comprising administering atherapeutically effective amount of a compound of claim 11 to a subjectin need thereof.
 22. A method for treating inflammation or aninflammation-associated disorder comprising administering atherapeutically effective amount of a compound of claim 12 to a subjectin need thereof.
 23. The method of claim 18 for treating inflammation.24. The method of claim 18 for treating an inflammation-associateddisorder.
 25. The method of claim 24 wherein the inflammation-associateddisorder is arthritis.
 26. The method of claim 24 wherein theinflammation-associated disorder is pain.
 27. The method of claim 24wherein the inflammation-associated disorder is fever.